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My scientific interests are broadly defined as everything related to protein folding, misfolding and non-folding. However, the passion is definitely the field of protein non-folding , which is related to the discovery of intrinsically disordered proteins (IDPs), analysis of their abundance in nature, characterization of their exceptional structural and functional plasticity, understanding of their vital roles in various biological processes, and establishing their involvement in the pathogenesis of multiple human diseases. These and related aspects of IDPs are analyzed by a combination of a wide spectrum of computational, bioinformatics, and experimental approaches of modern protein biophysics. Due to the high abundance of IDPs in various proteomes, the exceptional structural and functional plasticity of these proteins, and their intimate relations to the maladies' pathogenesis, it is almost impossible to find an area of protein science where IDPs would not play a noticeable role.
We have previously demonstrated the ability of the human vaginal strain Lactobacillus crispatus 2029 (LC2029) for strong adhesion to cervicovaginal epithelial cells, expression of the surface layer protein 2 (Slp2), and antagonistic activity against urogenital pathogens. Slp2 forms regular two-dimensional structure around the LC2029 cells,which is secreted into the medium and inhibits intestinal pathogen-induced activation of caspase-9 and caspase-3 in the human intestinal Caco-2 cells. Here, we elucidated the effects of soluble Slp2 on adhesion of proteobacteria pathogens inducing necrotizing enterocolitis (NEC), such as Escherichia coli ATCC E 2348/69, E. coli ATCC 31705, Salmonella Enteritidis ATCC 13076, Campylobacter jejuni ATCC 29428, and Pseudomonas aeruginosa ATCC 27853 to Caco-2 cells, as well as on growth promotion, differentiation, vascular endothelial growth factor (VEGF) production, and intestinal barrier function of Caco-2 cell monolayers. Slp2 acts as anti-adhesion agent for NEC-inducing proteobacteria, promotes growth of immature Caco-2 cells and their differentiation, and enhances expression and functional activity of sucrase, lactase, and alkaline phosphatase. Slp2 stimulates VEGF production, decreases paracellular permeability, and increases transepithelial electrical resistance, strengthening barrier function of Caco-2 cell monolayers. These data support the important role of Slp2 in the early postnatal development of the human small intestine enterocytes.
Vyacheslav M. Abramov; Igor V. Kosarev; Tatiana V. Priputnevich; Andrey V. Machulin; Tatiana N. Abashina; Irina O. Chikileva; Almira D. Donetskova; Kazuhide Takada; Vyacheslav G. Melnikov; Raisa N. Vasilenko; Valentin S. Khlebnikov; Vladimir A. Samoilenko; Ilya N. Nikonov; Gennady T. Sukhikh; Vladimir N. Uversky; Andrey V. Karlyshev. S-layer protein 2 of vaginal Lactobacillus crispatus 2029 enhances growth, differentiation, VEGF production and barrier functions in intestinal epithelial cell line Caco-2. International Journal of Biological Macromolecules 2021, 189, 410 -419.
AMA StyleVyacheslav M. Abramov, Igor V. Kosarev, Tatiana V. Priputnevich, Andrey V. Machulin, Tatiana N. Abashina, Irina O. Chikileva, Almira D. Donetskova, Kazuhide Takada, Vyacheslav G. Melnikov, Raisa N. Vasilenko, Valentin S. Khlebnikov, Vladimir A. Samoilenko, Ilya N. Nikonov, Gennady T. Sukhikh, Vladimir N. Uversky, Andrey V. Karlyshev. S-layer protein 2 of vaginal Lactobacillus crispatus 2029 enhances growth, differentiation, VEGF production and barrier functions in intestinal epithelial cell line Caco-2. International Journal of Biological Macromolecules. 2021; 189 ():410-419.
Chicago/Turabian StyleVyacheslav M. Abramov; Igor V. Kosarev; Tatiana V. Priputnevich; Andrey V. Machulin; Tatiana N. Abashina; Irina O. Chikileva; Almira D. Donetskova; Kazuhide Takada; Vyacheslav G. Melnikov; Raisa N. Vasilenko; Valentin S. Khlebnikov; Vladimir A. Samoilenko; Ilya N. Nikonov; Gennady T. Sukhikh; Vladimir N. Uversky; Andrey V. Karlyshev. 2021. "S-layer protein 2 of vaginal Lactobacillus crispatus 2029 enhances growth, differentiation, VEGF production and barrier functions in intestinal epithelial cell line Caco-2." International Journal of Biological Macromolecules 189, no. : 410-419.
Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma likely reflects the antigenic composition of local viral strains, we hypothesize that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to approximately 28,000 patients from the Expanded Access to Convalescent Plasma program (ClinicalTrials.gov number: NCT04338360) support this hypothesis. This work has implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge.© 2021. The Author(s).
Vladimir Uversky; Kunze Kl; Johnson Pw; Van Helmond N; Senefeld Jw; Petersen Mm; Klassen Sa; Wiggins Cc; Klompas Am; Bruno Ka; Mills Jr; Theel Es; Buras; Golafshar Ma; Sexton Ma; Diaz Soto Jc; Baker Se; Shepherd Jra; Verdun Nc; MarkS P; Paneth Ns; Fairweather D; Wright Rs; Van Buskirk Cm; Winters Jl; Stubbs Jr; Senese Ka; Pletsch MC; Buchholtz Za; Rea Rf; Herasevich V; Whelan Er; Clayburn Aj; Larson Kf; Ripoll Jg; Andersen Kj; Lesser Er; Vogt Mnp; Dennis Jj; Regimbal Rj; Bauer Pr; Blair Je; Casadevall A; Carter Re; Joyner Mj. Faculty Opinions recommendation of Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2021, 12, 1 .
AMA StyleVladimir Uversky, Kunze Kl, Johnson Pw, Van Helmond N, Senefeld Jw, Petersen Mm, Klassen Sa, Wiggins Cc, Klompas Am, Bruno Ka, Mills Jr, Theel Es, Buras, Golafshar Ma, Sexton Ma, Diaz Soto Jc, Baker Se, Shepherd Jra, Verdun Nc, MarkS P, Paneth Ns, Fairweather D, Wright Rs, Van Buskirk Cm, Winters Jl, Stubbs Jr, Senese Ka, Pletsch MC, Buchholtz Za, Rea Rf, Herasevich V, Whelan Er, Clayburn Aj, Larson Kf, Ripoll Jg, Andersen Kj, Lesser Er, Vogt Mnp, Dennis Jj, Regimbal Rj, Bauer Pr, Blair Je, Casadevall A, Carter Re, Joyner Mj. Faculty Opinions recommendation of Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2021; 12 (1):1.
Chicago/Turabian StyleVladimir Uversky; Kunze Kl; Johnson Pw; Van Helmond N; Senefeld Jw; Petersen Mm; Klassen Sa; Wiggins Cc; Klompas Am; Bruno Ka; Mills Jr; Theel Es; Buras; Golafshar Ma; Sexton Ma; Diaz Soto Jc; Baker Se; Shepherd Jra; Verdun Nc; MarkS P; Paneth Ns; Fairweather D; Wright Rs; Van Buskirk Cm; Winters Jl; Stubbs Jr; Senese Ka; Pletsch MC; Buchholtz Za; Rea Rf; Herasevich V; Whelan Er; Clayburn Aj; Larson Kf; Ripoll Jg; Andersen Kj; Lesser Er; Vogt Mnp; Dennis Jj; Regimbal Rj; Bauer Pr; Blair Je; Casadevall A; Carter Re; Joyner Mj. 2021. "Faculty Opinions recommendation of Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 12, no. 1: 1.
: Modern protein science is broadening horizons by moving toward the systemic description of proteins in their natural habitats. This implies a transition from a classical reductionist approach associated with consideration of the unique structure and specific biological activity of an individual protein in a purified form to studying entire proteomes and their functions. This mini-review provides a brief description of structural, functional, and expression proteomics, the dark proteome (or unfoldome), and some of the tools utilized in the analyses of proteomes.
Vladimir N. Uversky; Mohammed F. Alghamdi; Elrashdy M. Redwan. A Bird's-Eye View of Proteomics. Current Protein & Peptide Science 2021, 22, 1 .
AMA StyleVladimir N. Uversky, Mohammed F. Alghamdi, Elrashdy M. Redwan. A Bird's-Eye View of Proteomics. Current Protein & Peptide Science. 2021; 22 ():1.
Chicago/Turabian StyleVladimir N. Uversky; Mohammed F. Alghamdi; Elrashdy M. Redwan. 2021. "A Bird's-Eye View of Proteomics." Current Protein & Peptide Science 22, no. : 1.
In humans, the family of Bcl-2 associated athanogene (BAG) proteins includes six members characterized by exceptional multifunctionality and engagement in the pathogenesis of various diseases. All of them are capable of interacting with a multitude of often unrelated binding partners. Such binding promiscuity and related functional and pathological multifacetedness cannot be explained or understood within the frames of the classical “one protein–one structure–one function” model, which also fails to explain the presence of multiple isoforms generated for BAG proteins by alternative splicing or alternative translation initiation and their extensive posttranslational modifications. However, all these mysteries can be solved by taking into account the intrinsic disorder phenomenon. In fact, high binding promiscuity and potential to participate in a broad spectrum of interactions with multiple binding partners, as well as a capability to be multifunctional and multipathogenic, are some of the characteristic features of intrinsically disordered proteins and intrinsically disordered protein regions. Such functional proteins or protein regions lacking unique tertiary structures constitute a cornerstone of the protein structure-function continuum concept. The aim of this paper is to provide an overview of the functional roles of human BAG proteins from the perspective of protein intrinsic disorder which will provide a means for understanding their binding promiscuity, multifunctionality, and relation to the pathogenesis of various diseases.
Liberato Marzullo; Maria C. Turco; Vladimir N. Uversky. What's in the BAGs? Intrinsic disorder angle of the multifunctionality of the members of a family of chaperone regulators. Journal of Cellular Biochemistry 2021, 1 .
AMA StyleLiberato Marzullo, Maria C. Turco, Vladimir N. Uversky. What's in the BAGs? Intrinsic disorder angle of the multifunctionality of the members of a family of chaperone regulators. Journal of Cellular Biochemistry. 2021; ():1.
Chicago/Turabian StyleLiberato Marzullo; Maria C. Turco; Vladimir N. Uversky. 2021. "What's in the BAGs? Intrinsic disorder angle of the multifunctionality of the members of a family of chaperone regulators." Journal of Cellular Biochemistry , no. : 1.
BACKGROUND: The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity.OBJECTIVE: The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α-synuclein transmission in cultured cells and mouse models of Parkinson's disease.METHODS: Mouse primary hippocampal neurons were transduced with α-synuclein preformed fibrils to examine the effect of perampanel on the development of α-synuclein pathology and its mechanisms of action. An α-synuclein preformed fibril-injected mouse model was used to validate the effect of oral administration of perampanel on the α-synuclein pathology in vivo.RESULTS: Perampanel inhibited the development of α-synuclein pathology in mouse hippocampal neurons transduced with α-synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α-synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity-dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α-synuclein pathology in wild-type mice inoculated with α-synuclein preformed fibrils.CONCLUSION: Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease-modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.© 2021 International Parkinson and Movement Disorder Society.
Vladimir Uversky; Ueda J; Uemura N; Sawamura M; Taguchi T; Ikuno M; Kaji S; Taruno Y; Matsuzawa S; Yamakado H; Takahashi R. Faculty Opinions recommendation of Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2021, 36, 1 .
AMA StyleVladimir Uversky, Ueda J, Uemura N, Sawamura M, Taguchi T, Ikuno M, Kaji S, Taruno Y, Matsuzawa S, Yamakado H, Takahashi R. Faculty Opinions recommendation of Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2021; 36 (7):1.
Chicago/Turabian StyleVladimir Uversky; Ueda J; Uemura N; Sawamura M; Taguchi T; Ikuno M; Kaji S; Taruno Y; Matsuzawa S; Yamakado H; Takahashi R. 2021. "Faculty Opinions recommendation of Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 36, no. 7: 1.
An increasing number of proteins, which have neither regular secondary nor well-defined tertiary structures, have been found to be present in cells. The structure of these proteins is highly flexible and disordered under physiological (native) conditions, and they are called "intrinsically disordered" proteins (IDPs). Many of the IDPs are involved in interactions with other biomolecules such as DNA, RNA, carbohydrates, and proteins. While these IDPs are largely unstructured by themselves, marked conformational changes often occur upon binding to an interacting partner, which is known as the "coupled folding and binding mechanism", which enable them to change the conformation to become compatible with the shape of the multiple target biomolecules. We have studied the structure and interaction of eukaryotic transcription factors Sp1 and TAF4, and found that both of them have long intrinsically disordered regions (IDRs). One of the IDRs in Sp1 exhibited homo-oligomer formation. In addition, the same region was used for the interaction with another IDR found in the TAF4 molecule. In both cases, we have not detected any significant conformational change in that region, suggesting a prominent and novel binding mode for IDPs/IDRs, which are not categorized by the well-accepted concept of the coupled folding and binding mechanism.2020 THE BIOPHYSICAL SOCIETY OF JAPAN.
Vladimir Uversky; Hibino E; Hoshino M. Faculty Opinions recommendation of A novel mode of interaction between intrinsically disordered proteins. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2021, 17, 1 .
AMA StyleVladimir Uversky, Hibino E, Hoshino M. Faculty Opinions recommendation of A novel mode of interaction between intrinsically disordered proteins. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2021; 17 ():1.
Chicago/Turabian StyleVladimir Uversky; Hibino E; Hoshino M. 2021. "Faculty Opinions recommendation of A novel mode of interaction between intrinsically disordered proteins." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 17, no. : 1.
BACKGROUND: The non-receptor tyrosine kinase Abelson (Abl) is a key player in oncogenesis, with kinase inhibitors serving as paradigms of targeted therapy. Abl also is a critical regulator of normal development, playing conserved roles in regulating cell behavior, brain development and morphogenesis. Drosophila offers a superb model for studying Abl's normal function, because, unlike mammals, there is only a single fly Abl family member. In exploring the mechanism of action of multi-domain scaffolding proteins like Abl, one route is to define the roles of their individual domains. Research into Abl's diverse roles in embryonic morphogenesis revealed many surprises. For instance, kinase activity, while important, is not crucial for all Abl activities, and the C-terminal F-actin binding domain plays a very modest role. This turned our attention to one of Abl's least understood features-the long intrinsically-disordered region (IDR) linking Abl's kinase and F-actin binding domains. The past decade revealed unexpected, important roles for IDRs in diverse cell functions, as sites of posttranslational modifications, mediating multivalent interactions and enabling assembly of biomolecular condensates via phase separation. Previous work deleting conserved regions in Abl's IDR revealed an important role for a PXXP motif, but did not identify any other essential regions.METHODS: Here we extend this analysis by deleting the entire IDR, and asking whether Abl∆IDR rescues the diverse roles of Abl in viability and embryonic morphogenesis in Drosophila.RESULTS: This revealed that the IDR is essential for embryonic and adult viability, and for cell shape changes and cytoskeletal regulation during embryonic morphogenesis, and, most surprisingly, revealed a role in modulating protein stability.CONCLUSION: Our data provide new insights into the role of the IDR in an important signaling protein, the non-receptor kinase Abl, suggesting that it is essential for all aspects of protein function during embryogenesis, and revealing a role in protein stability. These data will stimulate new explorations of the mechanisms by which the IDR regulates Abl stability and function, both in Drosophila and also in mammals. They also will stimulate further interest in the broader roles IDRs play in diverse signaling proteins. Video
Vladimir Uversky; Rogers Em; Allred Sc; Peifer M. Faculty Opinions recommendation of Abelson kinase's intrinsically disordered region plays essential roles in protein function and protein stability. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 2021, 19, 1 .
AMA StyleVladimir Uversky, Rogers Em, Allred Sc, Peifer M. Faculty Opinions recommendation of Abelson kinase's intrinsically disordered region plays essential roles in protein function and protein stability. Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature. 2021; 19 (1):1.
Chicago/Turabian StyleVladimir Uversky; Rogers Em; Allred Sc; Peifer M. 2021. "Faculty Opinions recommendation of Abelson kinase's intrinsically disordered region plays essential roles in protein function and protein stability." Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature 19, no. 1: 1.
The universal chirality is the commonly accepted view of nature. Biological chirality is the distinct part of the more general phenomena. Following this view, all living organisms are characterized by the non-equilibrium state of their molecular constituents. From the thermodynamic perspective, the non-equilibrium state of biomolecular ensemble holds inevitable consequences being the substrate of spontaneous reactions directed to equilibrium (not associated with life) state. At the protein level, spontaneous biological reactions represent the natural part of proteins' post-translational modifications (PTMs). The essential contribution to the origin and maintenance of the non-equilibrium state belongs to prevalent bio-molecular chirality. Correspondently, spontaneous PTMs such as racemization and glycation, working against life-supporting prevalent chirality, are known as the significant determinants of protein misfolding, dysfunctions, and aggregation. Accumulation of aberrant protein during life-span allows consideration of time-dependent spontaneous racemization and glycation as protein aging. Spontaneous PTMs of proteins is occurring in the interaction with other forms of enzymatic and non-enzymatic PTMs. In this review, we are considering the contribution of spontaneous racemization and non-enzymatic glycosylation to protein aging.
Victor Vasilyevich Dyakin; Vladimir Nikolaevich Uversky. Spontaneous Determinants of Protein Aging Mini Review. 2021, 1 .
AMA StyleVictor Vasilyevich Dyakin, Vladimir Nikolaevich Uversky. Spontaneous Determinants of Protein Aging Mini Review. . 2021; ():1.
Chicago/Turabian StyleVictor Vasilyevich Dyakin; Vladimir Nikolaevich Uversky. 2021. "Spontaneous Determinants of Protein Aging Mini Review." , no. : 1.
Background: Single nucleotide polymorphisms (SNPs) in the SLC10A1 gene, coding for a functional receptor of hepatitis B virus (HBV), sodium taurocholate co-transporting polypeptide (NTCP), may influence the susceptibility, the outcome, and disease course of HBV infection in some populations. Aim: to determine the prevalence of SNPs of NTCP gene, rs2296651 and rs943277, and their relationship with chronic HBV infection in a group of Egyptian patients. Methods: 137 patients with HBV and 65 healthy controls were enrolled, and the patients were divided into two groups; group I chronic HBV infection (68 patients with normal ALT and minimal or no liver necroinflammation or fibrosis) and group II chronic hepatitis B (69 patients with elevated ALT and moderate or severe liver necroinflammation). They were subjected to full history taking, clinical examination, laboratory investigations, abdominal ultrasound, and liver stiffness measurement using both Echosens® Fibroscan and acoustic radiation force impulse (ARFI). Real time PCR TaqMan 5’ allelic discrimination assay was applied to detect the SNPs in NTCP gene, rs2296651 and rs943277. Results: On studying the rs2296651 variant, all controls and patients had genotype GG without any significant association with HBV infection or disease progression. However, the rs943277 variant in all controls and 98% of patients had genotype GA, except for two chronic HBV infection patients who had genotype AA, but no significant difference between patients and controls was found. The non-invasive methods for liver fibrosis assessment ARFI, AST/platelet's ratio (APRI), and fibrosis-4 score (FIB-4) could predict the stages of fibrosis in agreement with Fibroscan with AUCOR 0.8, 0.79, and 0.76, respectively. Conclusion: These findings may suggest that there is no relation between these SNPs of the NTCP gene and susceptibility or chronicity of HBV infection in the Egyptian population. We also suggest that the use of the non-invasive methods for liver fibrosis assessment, ARFI, FIB-4, and APRI may decrease the need for liver biopsies in prediction of significant hepatic fibrosis in chronic HBV patients.
Maissa El Said El Raziky; Naglaa Ali Zayed; Yasmin Saad Ibrahim; Fatma Elrashdy; Rasha Mohamad Hosny Shahin; Mohamed Hassany; Magdy El Serafy; Wahid Doss; Vladimir N. Uversky; Ayman Yosry; Hadeel Gamal Eldeen. Association Analysis of Genetic Variants of Sodium Taurocholate Co-Transporting Polypeptide NTCP Gene (SLC10A1) and HBV Infection Status in a Cohort of Egyptian Patients. 2021, 1 .
AMA StyleMaissa El Said El Raziky, Naglaa Ali Zayed, Yasmin Saad Ibrahim, Fatma Elrashdy, Rasha Mohamad Hosny Shahin, Mohamed Hassany, Magdy El Serafy, Wahid Doss, Vladimir N. Uversky, Ayman Yosry, Hadeel Gamal Eldeen. Association Analysis of Genetic Variants of Sodium Taurocholate Co-Transporting Polypeptide NTCP Gene (SLC10A1) and HBV Infection Status in a Cohort of Egyptian Patients. . 2021; ():1.
Chicago/Turabian StyleMaissa El Said El Raziky; Naglaa Ali Zayed; Yasmin Saad Ibrahim; Fatma Elrashdy; Rasha Mohamad Hosny Shahin; Mohamed Hassany; Magdy El Serafy; Wahid Doss; Vladimir N. Uversky; Ayman Yosry; Hadeel Gamal Eldeen. 2021. "Association Analysis of Genetic Variants of Sodium Taurocholate Co-Transporting Polypeptide NTCP Gene (SLC10A1) and HBV Infection Status in a Cohort of Egyptian Patients." , no. : 1.
The devastating impact of the ongoing coronavirus disease 2019 (COVID-19) on public health, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has made fighting of the COVID-19 pandemic is a top priority in medical research and pharmaceutical development. Surveillance of SARS-CoV-2 mutations is essential for the comprehension of SARS-CoV-2 variant diversity and their impact on virulence and pathogenicity. The SARS-CoV-2 open reading frame 10 (ORF10) protein interacts with multiple human proteins CUL2, ELOB, ELOC, MAP7D1, PPT1, RBX1, THTPA, TIMM8B, and ZYG11B expressed in the lung tissues. Mutations and co-mutations in the emerging SARS-CoV-2 ORF10 variants are expected to impact the severity of the virus and its associated consequences. In this article, We highlight 128 single mutations and 35 co-mutations in the unique SARS-CoV-2 ORF10 variants in this article. The possible predicted effects of these mutations and co-mutations on the secondary structure of ORF10 variants and host protein interactomes are presented. The findings highlight the possible effects of mutations and co-mutations on the emerging 140 ORF10 unique variants from secondary structure and intrinsic protein disorder perspectives.
Sk. Sarif Hassan; Kenneth Lundstrom; Ángel Serrano-Aroca; Parise Adadi; Alaa Aljabali; ElRashdy Redwan; Amos Lal; Ramesh Kandimalla; Tarek El-Aziz; Pabitra Choudhury; Gajendra Azad; Samendra Sherchan; Murtaza Tambuwala; Gaurav Chauhan; Kazuo Takayama; Debmalya Barh; Giorgio Palù; Pallab Basu; Vladimir N Uversky. Emergence of Unique SARS-CoV-2 ORF10 Variants and Their Impact on Protein Structure and Function. 2021, 1 .
AMA StyleSk. Sarif Hassan, Kenneth Lundstrom, Ángel Serrano-Aroca, Parise Adadi, Alaa Aljabali, ElRashdy Redwan, Amos Lal, Ramesh Kandimalla, Tarek El-Aziz, Pabitra Choudhury, Gajendra Azad, Samendra Sherchan, Murtaza Tambuwala, Gaurav Chauhan, Kazuo Takayama, Debmalya Barh, Giorgio Palù, Pallab Basu, Vladimir N Uversky. Emergence of Unique SARS-CoV-2 ORF10 Variants and Their Impact on Protein Structure and Function. . 2021; ():1.
Chicago/Turabian StyleSk. Sarif Hassan; Kenneth Lundstrom; Ángel Serrano-Aroca; Parise Adadi; Alaa Aljabali; ElRashdy Redwan; Amos Lal; Ramesh Kandimalla; Tarek El-Aziz; Pabitra Choudhury; Gajendra Azad; Samendra Sherchan; Murtaza Tambuwala; Gaurav Chauhan; Kazuo Takayama; Debmalya Barh; Giorgio Palù; Pallab Basu; Vladimir N Uversky. 2021. "Emergence of Unique SARS-CoV-2 ORF10 Variants and Their Impact on Protein Structure and Function." , no. : 1.
Elrashdy M. Redwan; Mohammed F. Alghamdi; Tarek Mohamed Abd El-Aziz; Parise Adadi; Alaa A.A. Aljabali; Diksha Attrish; Gajendra Kumar Azad; Wagner Baetas-Da-Cruz; Debmalya Barh; Nicolas G. Bazan; Adam M. Brufsky; Gaurav Chauhan; S.K. Sarif Hassan; Ramesh Kandimalla; Amos Lal; Kenneth Lundstrom; Yogendra Kumar Mishra; Pabitra Pal Choudhury; Giorgio Palù; Pritam K. Panda; Damiano Pizzol; Nima Rezaei; Ángel Serrano-Aroca; Samendra P. Sherchan; Murat Seyran; Kazuo Takayama; Murtaza M. Tambuwala; Bruce D. Uhal; Vladimir N. Uversky. The mechanism behind flaring/triggering of autoimmunity disorders associated with COVID-19. Autoimmunity Reviews 2021, 20, 102909 -102909.
AMA StyleElrashdy M. Redwan, Mohammed F. Alghamdi, Tarek Mohamed Abd El-Aziz, Parise Adadi, Alaa A.A. Aljabali, Diksha Attrish, Gajendra Kumar Azad, Wagner Baetas-Da-Cruz, Debmalya Barh, Nicolas G. Bazan, Adam M. Brufsky, Gaurav Chauhan, S.K. Sarif Hassan, Ramesh Kandimalla, Amos Lal, Kenneth Lundstrom, Yogendra Kumar Mishra, Pabitra Pal Choudhury, Giorgio Palù, Pritam K. Panda, Damiano Pizzol, Nima Rezaei, Ángel Serrano-Aroca, Samendra P. Sherchan, Murat Seyran, Kazuo Takayama, Murtaza M. Tambuwala, Bruce D. Uhal, Vladimir N. Uversky. The mechanism behind flaring/triggering of autoimmunity disorders associated with COVID-19. Autoimmunity Reviews. 2021; 20 (10):102909-102909.
Chicago/Turabian StyleElrashdy M. Redwan; Mohammed F. Alghamdi; Tarek Mohamed Abd El-Aziz; Parise Adadi; Alaa A.A. Aljabali; Diksha Attrish; Gajendra Kumar Azad; Wagner Baetas-Da-Cruz; Debmalya Barh; Nicolas G. Bazan; Adam M. Brufsky; Gaurav Chauhan; S.K. Sarif Hassan; Ramesh Kandimalla; Amos Lal; Kenneth Lundstrom; Yogendra Kumar Mishra; Pabitra Pal Choudhury; Giorgio Palù; Pritam K. Panda; Damiano Pizzol; Nima Rezaei; Ángel Serrano-Aroca; Samendra P. Sherchan; Murat Seyran; Kazuo Takayama; Murtaza M. Tambuwala; Bruce D. Uhal; Vladimir N. Uversky. 2021. "The mechanism behind flaring/triggering of autoimmunity disorders associated with COVID-19." Autoimmunity Reviews 20, no. 10: 102909-102909.
Two adenovirus-based vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S, and two mRNA-based vaccines, BNT162b2 and mRNA.1273, have been approved by the European Medicines Agency (EMA), and are invaluable in preventing and reducing the incidence of coronavirus disease-2019 (COVID-19). Recent reports have pointed to thrombosis with associated thrombocytopenia as an adverse effect occurring at a low frequency in some individuals after vaccination. The causes of such events may be related to SARS-CoV-2 spike protein interactions with different C-type lectin receptors, heparan sulfate proteoglycans (HSPGs) and the CD147 receptor, or to different soluble splice variants of the spike protein, adenovirus vector interactions with the CD46 receptor or platelet factor 4 antibodies. Similar findings have been reported for several viral diseases after vaccine administration. In addition, immunological mechanisms elicited by viral vectors related to cellular delivery could play a relevant role in individuals with certain genetic backgrounds. Although rare, the potential COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) requires immediate validation, especially in risk groups, such as the elderly, chronic smokers, and individuals with pre-existing incidences of thrombocytopenia; and if necessary, a reformulation of existing vaccines.
Kenneth Lundstrom; Debmalya Barh; Bruce Uhal; Kazuo Takayama; Alaa Aljabali; Tarek Abd El-Aziz; Amos Lal; ElRashdy Redwan; Parise Adadi; Gaurav Chauhan; Samendra Sherchan; Gajendra Azad; Nima Rezaei; Ángel Serrano-Aroca; Nicolas Bazan; Sk Hassan; Pritam Panda; Pabitra Pal Choudhury; Damiano Pizzol; Ramesh Kandimalla; Wagner Baetas-Da-Cruz; Yogendra Mishra; Giorgio Palu; Adam Brufsky; Murtaza Tambuwala; Vladimir Uversky. COVID-19 Vaccines and Thrombosis—Roadblock or Dead-End Street? Biomolecules 2021, 11, 1020 .
AMA StyleKenneth Lundstrom, Debmalya Barh, Bruce Uhal, Kazuo Takayama, Alaa Aljabali, Tarek Abd El-Aziz, Amos Lal, ElRashdy Redwan, Parise Adadi, Gaurav Chauhan, Samendra Sherchan, Gajendra Azad, Nima Rezaei, Ángel Serrano-Aroca, Nicolas Bazan, Sk Hassan, Pritam Panda, Pabitra Pal Choudhury, Damiano Pizzol, Ramesh Kandimalla, Wagner Baetas-Da-Cruz, Yogendra Mishra, Giorgio Palu, Adam Brufsky, Murtaza Tambuwala, Vladimir Uversky. COVID-19 Vaccines and Thrombosis—Roadblock or Dead-End Street? Biomolecules. 2021; 11 (7):1020.
Chicago/Turabian StyleKenneth Lundstrom; Debmalya Barh; Bruce Uhal; Kazuo Takayama; Alaa Aljabali; Tarek Abd El-Aziz; Amos Lal; ElRashdy Redwan; Parise Adadi; Gaurav Chauhan; Samendra Sherchan; Gajendra Azad; Nima Rezaei; Ángel Serrano-Aroca; Nicolas Bazan; Sk Hassan; Pritam Panda; Pabitra Pal Choudhury; Damiano Pizzol; Ramesh Kandimalla; Wagner Baetas-Da-Cruz; Yogendra Mishra; Giorgio Palu; Adam Brufsky; Murtaza Tambuwala; Vladimir Uversky. 2021. "COVID-19 Vaccines and Thrombosis—Roadblock or Dead-End Street?" Biomolecules 11, no. 7: 1020.
Chandipura virus (CHPV, a member of the Rhabdoviridae family) is an emerging pathogen that causes rapidly progressing influenza-like illness and acute encephalitis often leading to coma and death of the human host. Given several CHPV outbreaks in Indian sub-continent, recurring sporadic cases, neurological manifestation, and high mortality rate of this infection, CHPV is gaining global attention. The ‘dark proteome’ includes the whole proteome with special emphasis on intrinsically disordered proteins (IDP) and IDP regions (IDPR), which are proteins or protein regions that lack unique (or ordered) three-dimensional structures within the cellular milieu. These proteins/regions, however, play a number of vital roles in various biological processes, such as cell cycle regulation, control of signaling pathways, etc. and, therefore, are implicated in many human diseases. IDPs and IPPRs are also abundantly found in many viral proteins enabling their multifunctional roles in the viral life cycles and their capability to highjack various host systems. The unknown abundance of IDP and IDPR in CHPV, therefore, prompted us to analyze the dark proteome of this virus. Our analysis revealed a varying degree of disorder in all five CHPV proteins, with the maximum level of intrinsic disorder propensity being found in Phosphoprotein (P). We have also shown the flexibility of P protein using extensive molecular dynamics simulations up to 500 ns (ns). Furthermore, our analysis also showed the abundant presence of the disorder-based binding regions (also known as molecular recognition features, MoRFs) in CHPV proteins. The identification of IDPs/IDPRs in CHPV proteins suggests that their disordered regions may function as potential interacting domains and may also serve as novel targets for disorder-based drug designs.
Nishi R. Sharma; Kundlik Gadhave; Prateek Kumar; Mohammad Saif; M. Khan; Debi P. Sarkar; Vladimir N. Uversky; Rajanish Giri. Analysis of the dark proteome of Chandipura virus reveals maximum propensity for intrinsic disorder in phosphoprotein. Scientific Reports 2021, 11, 1 -17.
AMA StyleNishi R. Sharma, Kundlik Gadhave, Prateek Kumar, Mohammad Saif, M. Khan, Debi P. Sarkar, Vladimir N. Uversky, Rajanish Giri. Analysis of the dark proteome of Chandipura virus reveals maximum propensity for intrinsic disorder in phosphoprotein. Scientific Reports. 2021; 11 (1):1-17.
Chicago/Turabian StyleNishi R. Sharma; Kundlik Gadhave; Prateek Kumar; Mohammad Saif; M. Khan; Debi P. Sarkar; Vladimir N. Uversky; Rajanish Giri. 2021. "Analysis of the dark proteome of Chandipura virus reveals maximum propensity for intrinsic disorder in phosphoprotein." Scientific Reports 11, no. 1: 1-17.
The multi-level organization of nature is self-evident: proteins do interact among them to give rise to an organized metabolism, while in the same time each protein (a single node of such interaction network) is itself a network of interacting amino-acid residues allowing coordinated motion of the macromolecule and systemic effect as allosteric behavior. Similar pictures can be drawn for structure and function of cells, organs, tissues, and ecological systems. The majority of biologists are used to think that causally relevant events originate from the lower level (the molecular one) in the form of perturbations, that “climb up” the hierarchy reaching the ultimate layer of macroscopic behavior (e.g., causing a specific disease). Such causative model, stemming from the usual genotype-phenotype distinction, is not the only one. As a matter of fact, one can observe top-down, bottom-up, as well as middle-out perturbation/control trajectories. The recent complex network studies allow to go further the pure qualitative observation of the existence of both non-linear and non-bottom-up processes and to uncover the deep nature of multi-level organization. Here, taking as paradigm protein structural and interaction networks, we review some of the most relevant results dealing with between networks communication shedding light on the basic principles of complex system control and dynamics and offering a more realistic frame of causation in biology.
Vladimir N. Uversky; Alessandro Giuliani. Networks of Networks: An Essay on Multi-Level Biological Organization. Frontiers in Genetics 2021, 12, 1 .
AMA StyleVladimir N. Uversky, Alessandro Giuliani. Networks of Networks: An Essay on Multi-Level Biological Organization. Frontiers in Genetics. 2021; 12 ():1.
Chicago/Turabian StyleVladimir N. Uversky; Alessandro Giuliani. 2021. "Networks of Networks: An Essay on Multi-Level Biological Organization." Frontiers in Genetics 12, no. : 1.
Several hypotheses have been presented on the origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from its identification as the agent causing the current coronavirus disease 19 (COVID-19) pandemic. So far, no hypothesis has managed to identify the origin, and the issue has resurfaced. Here we have unfolded a pattern of distribution of several mutations in the SARS-CoV-2 proteins across different continents comprising 24 geo-locations. The results showed an evenly uneven distribution of unique protein variants, distinct mutations, unique frequency of common conserved residues, and mutational residues across the 24 geo-locations. Furthermore, ample mutations were identified in the evolutionarily conserved invariant regions in the SARS-CoV-2 proteins across almost all geo-locations we have considered. This pattern of mutations potentially breaches the law of evolutionary conserved functional units of the beta-coronavirus genus. These mutations may lead to several novel SARS-CoV-2 variants with a high degree of transmissibility and virulence. A thorough investigation on the origin and characteristics of SARS-CoV-2 needs to be conducted in the interest of science and to be prepared to meet the challenges of potential future pandemics.
Sk Sarif Hassan; Vaishnavi Kodakandla; Elrashdy M. Redwan; Kenneth Lundstrom; Pabitra Pal Choudhury; Ángel Serrano-Aroca Aroca; Gajendra Kumar Azad; Alaa A.A. Aljabali; Giorgio Palu; Tarek Mohamed Abd El-Aziz; Debmalya Barh; Bruce D. Uhal; Parise Adadi; Kazuo Takayama; Nicolas G. Bazan; Murtaza Tambuwala; Samendra P. Sherchan; Amos Lal; Gaurav Chauhan; Wagner Baetas-Da-Cruz; Vladimir N. Uversky. Non-Uniform Aspects of SARS-CoV-2 Intraspecies Evolution Reopen Questions on Its Origin. 2021, 1 .
AMA StyleSk Sarif Hassan, Vaishnavi Kodakandla, Elrashdy M. Redwan, Kenneth Lundstrom, Pabitra Pal Choudhury, Ángel Serrano-Aroca Aroca, Gajendra Kumar Azad, Alaa A.A. Aljabali, Giorgio Palu, Tarek Mohamed Abd El-Aziz, Debmalya Barh, Bruce D. Uhal, Parise Adadi, Kazuo Takayama, Nicolas G. Bazan, Murtaza Tambuwala, Samendra P. Sherchan, Amos Lal, Gaurav Chauhan, Wagner Baetas-Da-Cruz, Vladimir N. Uversky. Non-Uniform Aspects of SARS-CoV-2 Intraspecies Evolution Reopen Questions on Its Origin. . 2021; ():1.
Chicago/Turabian StyleSk Sarif Hassan; Vaishnavi Kodakandla; Elrashdy M. Redwan; Kenneth Lundstrom; Pabitra Pal Choudhury; Ángel Serrano-Aroca Aroca; Gajendra Kumar Azad; Alaa A.A. Aljabali; Giorgio Palu; Tarek Mohamed Abd El-Aziz; Debmalya Barh; Bruce D. Uhal; Parise Adadi; Kazuo Takayama; Nicolas G. Bazan; Murtaza Tambuwala; Samendra P. Sherchan; Amos Lal; Gaurav Chauhan; Wagner Baetas-Da-Cruz; Vladimir N. Uversky. 2021. "Non-Uniform Aspects of SARS-CoV-2 Intraspecies Evolution Reopen Questions on Its Origin." , no. : 1.
Prevention of amyloid β peptide (Aβ) deposition via facilitation of Aβ binding to its natural depot, human serum albumin (HSA), is a promising approach to preclude Alzheimer’s disease (AD) onset and progression. Previously, we demonstrated the ability of natural HSA ligands, fatty acids, to improve the affinity of this protein to monomeric Aβ by a factor of 3 (BBRC, 510(2), 248–253). Using plasmon resonance spectroscopy, we show here that another HSA ligand related to AD pathogenesis, serotonin (SRO), increases the affinity of the Aβ monomer to HSA by a factor of 7/17 for Aβ40/Aβ42, respectively. Meanwhile, the structurally homologous SRO precursor, tryptophan (TRP), does not affect HSA’s affinity to monomeric Aβ, despite slowdown of the association and dissociation processes. Crosslinking with glutaraldehyde and dynamic light scattering experiments reveal that, compared with the TRP-induced effects, SRO binding causes more marked changes in the quaternary structure of HSA. Furthermore, molecular docking reveals distinct structural differences between SRO/TRP complexes with HSA. The disintegration of the serotonergic system during AD pathogenesis may contribute to Aβ release from HSA in the central nervous system due to impairment of the SRO-mediated Aβ trapping by HSA.
Ekaterina Litus; Alexey Kazakov; Evgenia Deryusheva; Ekaterina Nemashkalova; Marina Shevelyova; Aliya Nazipova; Maria Permyakova; Elena Raznikova; Vladimir Uversky; Sergei Permyakov. Serotonin Promotes Serum Albumin Interaction with the Monomeric Amyloid β Peptide. International Journal of Molecular Sciences 2021, 22, 5896 .
AMA StyleEkaterina Litus, Alexey Kazakov, Evgenia Deryusheva, Ekaterina Nemashkalova, Marina Shevelyova, Aliya Nazipova, Maria Permyakova, Elena Raznikova, Vladimir Uversky, Sergei Permyakov. Serotonin Promotes Serum Albumin Interaction with the Monomeric Amyloid β Peptide. International Journal of Molecular Sciences. 2021; 22 (11):5896.
Chicago/Turabian StyleEkaterina Litus; Alexey Kazakov; Evgenia Deryusheva; Ekaterina Nemashkalova; Marina Shevelyova; Aliya Nazipova; Maria Permyakova; Elena Raznikova; Vladimir Uversky; Sergei Permyakov. 2021. "Serotonin Promotes Serum Albumin Interaction with the Monomeric Amyloid β Peptide." International Journal of Molecular Sciences 22, no. 11: 5896.
In this work, we put forward a hypothesis about the decisive role of multivalent nonspecific interactions in the early stages of PML body formation. Our analysis of the PML isoform sequences showed that some of the PML isoforms, primarily PML-II, are prone to phase separation due to their polyampholytic properties and the disordered structure of their C-terminal domains. The similarity of the charge properties of the C-terminal domains of PML-II and PML-VI isoforms made it possible for the first time to detect migration of PML-VI from PML bodies to the periphery of the cell nucleus, similar to the migration of PML-II isoforms. We found a population of “small” (area less than 1 µm2) spherical PML bodies with high dynamics of PML isoforms exchange with nucleoplasm and a low fraction of immobilized proteins, which indicates their liquid state properties. Such structures can act as “seeds” of functionally active PML bodies, providing the necessary concentration of PML isoforms for the formation of intermolecular disulfide bonds between PML monomers. FRAP analysis of larger bodies of toroidal topology showed the existence of an insoluble scaffold in their structure. The hypothesis about the role of nonspecific multiple weak interactions in the formation of PML bodies is further supported by the change in the composition of the scaffold proteins of PML bodies, but not their solidification, under conditions of induction of dimerization of PML isoforms under oxidative stress. Using the colocalization of ALT-associated PML bodies (APBs) with TRF1, we identified APBs and showed the difference in the dynamic properties of APBs and canonical PML bodies.
Alexander Fonin; Sergey Silonov; Olesya Shpironok; Iuliia Antifeeva; Alexey Petukhov; Anna Romanovich; Irina Kuznetsova; Vladimir Uversky; Konstantin Turoverov. The Role of Non-Specific Interactions in Canonical and ALT-Associated PML-Bodies Formation and Dynamics. International Journal of Molecular Sciences 2021, 22, 5821 .
AMA StyleAlexander Fonin, Sergey Silonov, Olesya Shpironok, Iuliia Antifeeva, Alexey Petukhov, Anna Romanovich, Irina Kuznetsova, Vladimir Uversky, Konstantin Turoverov. The Role of Non-Specific Interactions in Canonical and ALT-Associated PML-Bodies Formation and Dynamics. International Journal of Molecular Sciences. 2021; 22 (11):5821.
Chicago/Turabian StyleAlexander Fonin; Sergey Silonov; Olesya Shpironok; Iuliia Antifeeva; Alexey Petukhov; Anna Romanovich; Irina Kuznetsova; Vladimir Uversky; Konstantin Turoverov. 2021. "The Role of Non-Specific Interactions in Canonical and ALT-Associated PML-Bodies Formation and Dynamics." International Journal of Molecular Sciences 22, no. 11: 5821.
Open reading frame 8 (ORF8) protein is one of the most evolving accessory proteins in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). It was previously reported that the ORF8 protein inhibits presentation of viral antigens by the major histocompatibility complex class I (MHC-I) and interacts with host factors involved in pulmonary inflammation. The ORF8 protein assists SARS-CoV-2 to evade immunity and replication. Among many contributing mutations, Q27STOP, a mutation in the ORF8 protein defines the B.1.1.7 lineage of SARS-CoV-2, which is engendering the second wave of COVID-19. In the present study, 47 unique truncated ORF8 proteins (T-ORF8) due to the Q27STOP mutations were identified among 49055 available B.1.1.7 SARS-CoV-2 sequences. The results show that only one of the 47 T-ORF8 variants spread to over 57 geo-locations in North America, and other continents which includes Africa, Asia, Europe and South America. Based on various quantitative features such as amino acid homology, polar/non-polar sequence homology, Shannon entropy conservation, and other physicochemical properties of all specific 47 T-ORF8 protein variants, a collection of nine possible T-ORF8 unique variants were defined. The question of whether T-ORF8 variants work similarly to ORF8 has yet to be investigated. A positive response to the question could exacerbate future COVID-19 waves, necessitating severe containment measures.
Sk. Sarif Hassan; Vaishnavi Kodakandla; Elrashdy M. Redwan; Kenneth Lundstrom; Pabitra Pal Choudhury; Tarek Mohamed Abd El-Aziz; Kazuo Takayama; Ramesh Kandimalla; Amos Lal; Ángel Serrano-Aroca; Gajendra Kumar Azad; Alaa A. A. Aljabali; Giorgio Palu; Gaurav Chauhan; Parise Adadi; Murtaza Tambuwala; Adam M. Brufsky; Wagner Baetas-Da-Cruz; Debmalya Barh; Nicolas G Bazan; Vladimir N. Uversky. An Issue of Concern: Unique Truncated ORF8 Protein Variants of SARS-CoV-2. 2021, 1 .
AMA StyleSk. Sarif Hassan, Vaishnavi Kodakandla, Elrashdy M. Redwan, Kenneth Lundstrom, Pabitra Pal Choudhury, Tarek Mohamed Abd El-Aziz, Kazuo Takayama, Ramesh Kandimalla, Amos Lal, Ángel Serrano-Aroca, Gajendra Kumar Azad, Alaa A. A. Aljabali, Giorgio Palu, Gaurav Chauhan, Parise Adadi, Murtaza Tambuwala, Adam M. Brufsky, Wagner Baetas-Da-Cruz, Debmalya Barh, Nicolas G Bazan, Vladimir N. Uversky. An Issue of Concern: Unique Truncated ORF8 Protein Variants of SARS-CoV-2. . 2021; ():1.
Chicago/Turabian StyleSk. Sarif Hassan; Vaishnavi Kodakandla; Elrashdy M. Redwan; Kenneth Lundstrom; Pabitra Pal Choudhury; Tarek Mohamed Abd El-Aziz; Kazuo Takayama; Ramesh Kandimalla; Amos Lal; Ángel Serrano-Aroca; Gajendra Kumar Azad; Alaa A. A. Aljabali; Giorgio Palu; Gaurav Chauhan; Parise Adadi; Murtaza Tambuwala; Adam M. Brufsky; Wagner Baetas-Da-Cruz; Debmalya Barh; Nicolas G Bazan; Vladimir N. Uversky. 2021. "An Issue of Concern: Unique Truncated ORF8 Protein Variants of SARS-CoV-2." , no. : 1.
Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19 in several countries. By acting as a substrate for RdRp, favipiravir gets incorporated into the nascent viral RNA and prevents strand extension. A high mutation rate of SARS-CoV-2 RdRp may facilitate antigenic drift as an answer to the host immune response, thereby generating resistance of virus to favipiravir. Therefore, it is extremely crucial to predict potential mutational sites in the RdRp and the emergence of structural modifications contributing to drug resistance. Here, we used high-throughput interface-based protein design to generate >100,000 designs and identify mutation hotspot residues in the favipiravir-binding site of RdRp. Several mutants had lower binding affinities to favipiravir, out of which hotspot residues with a high propensity to undergo positive selection were identified. The results showed that the designs retained an average of 97 to 98% sequence identity, suggesting that SARS-CoV-2 can develop favipiravir resistance with just a few mutations. Notably, we observed that out of 134 mutations predicted designs, 63 specific mutations were already present in the CoV-GLUE database, thus attaining ~47% correlation match with the clinical sequencing data. The findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir and management of COVID-19. Furthermore, they can help develop exhaustive strategies for robust antiviral design and discovery.
Aditya K. Padhi; Jagneshwar Dandapat; Vladimir N. Uversky; Timir Tripathi. Structural Proteomics-Driven Targeted Design of Favipiravir-Binding Site in The RdRp of SARS-CoV-2 Unravels Susceptible Hotspots and Resistance Mutations. 2021, 1 .
AMA StyleAditya K. Padhi, Jagneshwar Dandapat, Vladimir N. Uversky, Timir Tripathi. Structural Proteomics-Driven Targeted Design of Favipiravir-Binding Site in The RdRp of SARS-CoV-2 Unravels Susceptible Hotspots and Resistance Mutations. . 2021; ():1.
Chicago/Turabian StyleAditya K. Padhi; Jagneshwar Dandapat; Vladimir N. Uversky; Timir Tripathi. 2021. "Structural Proteomics-Driven Targeted Design of Favipiravir-Binding Site in The RdRp of SARS-CoV-2 Unravels Susceptible Hotspots and Resistance Mutations." , no. : 1.
Background Endolysins of a number of bacteriophages, including coliphages T5, RB43, and RB49, target the peptidoglycans of the bacterial cell wall. The backbone of these bacterial peptidoglycans consist of alternating N-acetylglucosamine and N-acetylmuramic acid residues that is further “reinforced” by the peptide subunits. Because of the mesh-like structure and insolubility of peptidoglycans, the processes of the peptidoglycan binding and hydrolysis by enzymes cannot be studied by spectral methods. To overcome these issues we synthesized and analyzed here one of the simplest water soluble peptidoglycan mimetics. Methods A compound has been synthesized that mimics the peptidoglycan fragment of the bacterial cell wall, N-acetylglucosaminyl-β(1-4)-N-acetylmuramoyl-l-alanyl-γ-d-glutamyl-l-alanyl-d-alanine. NMR was used to study the degradation of this peptidoglycan mimetic by lytic l-alanoyl-d-glutamate peptidases of colibacteriophages T5, RB43, and RB49 (EndoT5, EndoRB43, and EndoRB49, respectively). Results The resulting glycopeptide mimetic was shown to interact with the studied enzymes. Its hydrolysis occurred through the bond between l-Ala and d-Glu. This artificial substrate mimetic was hydrolyzed by enzymes at different rates, which decreased outside the pH optimum. The EndoT5 demonstrated the lowest hydrolysis rate, whereas the EndoRB49-driven hydrolysis was the fastest one, and EndoRB43 displayed an intermediate potency. These observations are consistent with the hypothesis that EndoRB49 is characterized by the lowest selectivity, and hence the potentially broader spectrum of the peptidoglycan types subjected to hydrolysis, which was put forward in the previous study. We also show that to hydrolyze this glycopeptide mimetic, enzymes approach the glycopeptide near the methyl groups of all three alanines.
Viatcheslav Azev; Alexey Chulin; Maxim Molchanov; Dmitry Prokhorov; Galina Mikoulinskaia; Vladimir N. Uversky; Viktor Kutyshenko. Chemical synthesis of peptidoglycan mimetic–disaccharide-tetrapeptide conjugate and its hydrolysis by bacteriophage T5, RB43 and RB49 L-alanyl-D-glutamate peptidases. PeerJ 2021, 9, e11480 .
AMA StyleViatcheslav Azev, Alexey Chulin, Maxim Molchanov, Dmitry Prokhorov, Galina Mikoulinskaia, Vladimir N. Uversky, Viktor Kutyshenko. Chemical synthesis of peptidoglycan mimetic–disaccharide-tetrapeptide conjugate and its hydrolysis by bacteriophage T5, RB43 and RB49 L-alanyl-D-glutamate peptidases. PeerJ. 2021; 9 ():e11480.
Chicago/Turabian StyleViatcheslav Azev; Alexey Chulin; Maxim Molchanov; Dmitry Prokhorov; Galina Mikoulinskaia; Vladimir N. Uversky; Viktor Kutyshenko. 2021. "Chemical synthesis of peptidoglycan mimetic–disaccharide-tetrapeptide conjugate and its hydrolysis by bacteriophage T5, RB43 and RB49 L-alanyl-D-glutamate peptidases." PeerJ 9, no. : e11480.