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SARS-CoV-2, EBOV and emerging RNA viruses are amongst the most important global health threats; yet clinically approved antiviral drugs are available for only 10 of the more than 220 viruses known to infect humans.
Catherine S. Adamson; Kelly Chibale; Rebecca J. M. Goss; Marcel Jaspars; David J. Newman; Rosemary A. Dorrington. Antiviral drug discovery: preparing for the next pandemic. Chemical Society Reviews 2021, 50, 3647 -3655.
AMA StyleCatherine S. Adamson, Kelly Chibale, Rebecca J. M. Goss, Marcel Jaspars, David J. Newman, Rosemary A. Dorrington. Antiviral drug discovery: preparing for the next pandemic. Chemical Society Reviews. 2021; 50 (6):3647-3655.
Chicago/Turabian StyleCatherine S. Adamson; Kelly Chibale; Rebecca J. M. Goss; Marcel Jaspars; David J. Newman; Rosemary A. Dorrington. 2021. "Antiviral drug discovery: preparing for the next pandemic." Chemical Society Reviews 50, no. 6: 3647-3655.
In the midst of the SARS-CoV-2/Covid-19 outbreak the need for research into, and development of, antiviral agents is brought into sharp focus worldwide for scientists, governments and the public alike [...].
Catherine S. Adamson. Antiviral Agents: Discovery to Resistance. Viruses 2020, 12, 406 .
AMA StyleCatherine S. Adamson. Antiviral Agents: Discovery to Resistance. Viruses. 2020; 12 (4):406.
Chicago/Turabian StyleCatherine S. Adamson. 2020. "Antiviral Agents: Discovery to Resistance." Viruses 12, no. 4: 406.
The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors.
Catherine S. Adamson; Michael M. Nevels. Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function. Viruses 2020, 12, 110 .
AMA StyleCatherine S. Adamson, Michael M. Nevels. Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function. Viruses. 2020; 12 (1):110.
Chicago/Turabian StyleCatherine S. Adamson; Michael M. Nevels. 2020. "Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function." Viruses 12, no. 1: 110.
Viral interferon (IFN) antagonists are a diverse class of viral proteins that counteract the host IFN response, which is important for controlling viral infections. Viral IFN antagonists are often multifunctional proteins that perform vital roles in virus replication beyond IFN antagonism. The critical importance of viral IFN antagonists is highlighted by the fact that almost all viruses encode one of these proteins. Inhibition of viral IFN antagonists has the potential to exert pleiotropic antiviral effects and thus this important protein class represents a diverse plethora of novel therapeutic targets. To exploit this, we have successfully developed and executed a novel modular cell-based platform that facilitates the safe and rapid screening for inhibitors of a viral IFN antagonist of choice. The platform is based on two reporter cell-lines that provide a simple method to detect activation of IFN induction or signaling via an eGFP gene placed under the control of the IFNβ or an ISRE-containing promoter, respectively. Expression of a target IFN antagonist in the appropriate reporter cell-line will block the IFN response and hence eGFP expression. We hypothesized that addition of a compound that inhibits IFN antagonist function will release the block imposed on the IFN response and hence restore eGFP expression, providing a measurable parameter for high throughput screening (HTS). We demonstrate assay proof-of-concept by (i) exploiting hepatitis C virus (HCV) protease inhibitors to inhibit NS3-4A's capacity to block IFN induction and (ii) successfully executing two HTS targeting viral IFN antagonists that block IFN signaling; NS2 and IE1 from human respiratory syncytial virus (RSV) and cytomegalovirus (CMV) respectively, two clinically important viruses for which vaccine development has thus far been unsuccessful and new antivirals are required. Both screens performed robustly and Z′ Factor scores of >0.6 were achieved. We identified (i) four hit compounds that specifically inhibit RSV NS2's ability to block IFN signaling by mediating STAT2 degradation and exhibit modest antiviral activity and (ii) two hit compounds that interfere with IE1 transcription and significantly impair CMV replication. Overall, we demonstrate assay proof-of-concept as we target viral IFN antagonists from unrelated viruses and demonstrate its suitability for HTS.
Andri Vasou; Christina Paulus; Janina Narloch; Zoe O. Gage; Marie-Anne Rameix-Welti; Jean-François Eléouët; Michael Nevels; Richard Randall; Catherine S. Adamson. Modular cell-based platform for high throughput identification of compounds that inhibit a viral interferon antagonist of choice. Antiviral Research 2017, 150, 79 -92.
AMA StyleAndri Vasou, Christina Paulus, Janina Narloch, Zoe O. Gage, Marie-Anne Rameix-Welti, Jean-François Eléouët, Michael Nevels, Richard Randall, Catherine S. Adamson. Modular cell-based platform for high throughput identification of compounds that inhibit a viral interferon antagonist of choice. Antiviral Research. 2017; 150 ():79-92.
Chicago/Turabian StyleAndri Vasou; Christina Paulus; Janina Narloch; Zoe O. Gage; Marie-Anne Rameix-Welti; Jean-François Eléouët; Michael Nevels; Richard Randall; Catherine S. Adamson. 2017. "Modular cell-based platform for high throughput identification of compounds that inhibit a viral interferon antagonist of choice." Antiviral Research 150, no. : 79-92.
HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert -butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated. IMPORTANCE Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action.
Christopher Murgatroyd; Lisa Pirrie; Fanny Tran; Terry K. Smith; Nicholas J. Westwood; Catherine S. Adamson. Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396. Journal of Virology 2016, 90, 8181 -8197.
AMA StyleChristopher Murgatroyd, Lisa Pirrie, Fanny Tran, Terry K. Smith, Nicholas J. Westwood, Catherine S. Adamson. Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396. Journal of Virology. 2016; 90 (18):8181-8197.
Chicago/Turabian StyleChristopher Murgatroyd; Lisa Pirrie; Fanny Tran; Terry K. Smith; Nicholas J. Westwood; Catherine S. Adamson. 2016. "Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396." Journal of Virology 90, no. 18: 8181-8197.
Production of type I interferon (IFN) is an essential component of the innate immune response against invading pathogens. However, its production must be tightly regulated to avoid harmful effects. Compounds that modulate the IFN response are potentially valuable for a variety of applications due to IFN’s beneficial and detrimental roles. We developed and executed a cell-based high-throughput screen (HTS) targeting components that participate in and/or regulate the IRF3 and nuclear factor (NF)–κB branches of the IFN induction pathway. The assay detects activation of the IFN induction pathway via an enhanced green fluorescent protein (eGFP) reporter gene under the control of the IFNβ promoter and was optimized, miniaturized, and demonstrated suitable for HTS as robust Z′ factor scores of >0.6 were consistently achieved. A diversity screening set of 15,667 small molecules was assayed and two novel hit compounds validated that specifically inhibit the IFN induction pathway. We demonstrate that one of these compounds acts at or upstream of IRF3 phosphorylation. A second cell-based assay to detect activation of the IFN signaling (Jak-Stat) pathway via an eGFP reporter gene under the control of an IFN-stimulated response element (ISRE) containing MxA promoter also performed well (robust Z′ factor >0.7) and may therefore be similarly used to identify small molecules that modulate the IFN signaling pathway.
Zoe Olivia Gage; Andri Vasou; David Gray; Richard Randall; Catherine Sarah Adamson. Identification of Novel Inhibitors of the Type I Interferon Induction Pathway Using Cell-Based High-Throughput Screening. Journal of Biomolecular Screening 2016, 21, 978 -988.
AMA StyleZoe Olivia Gage, Andri Vasou, David Gray, Richard Randall, Catherine Sarah Adamson. Identification of Novel Inhibitors of the Type I Interferon Induction Pathway Using Cell-Based High-Throughput Screening. Journal of Biomolecular Screening. 2016; 21 (9):978-988.
Chicago/Turabian StyleZoe Olivia Gage; Andri Vasou; David Gray; Richard Randall; Catherine Sarah Adamson. 2016. "Identification of Novel Inhibitors of the Type I Interferon Induction Pathway Using Cell-Based High-Throughput Screening." Journal of Biomolecular Screening 21, no. 9: 978-988.
Many natural cyclic peptides have potent and potentially useful biological activities. Their use as therapeutic starting points is often limited by the quantities available, the lack of known biological targets and the practical limits on diversification to fine‐tune their properties. We report the use of enzymes from the cyanobactin family to heterocyclise and macrocyclise chemically synthesised substrates so as to allow larger‐scale syntheses and better control over derivatisation. We have made cyclic peptides containing orthogonal reactive groups, azide or dehydroalanine, that allow chemical diversification, including the use of fluorescent labels that can help in target identification. We show that the enzymes are compatible and efficient with such unnatural substrates. The combination of chemical synthesis and enzymatic transformation could help renew interest in investigating natural cyclic peptides with biological activity, as well as their unnatural analogues, as therapeutics.
Emilia Oueis; Catherine Adamson; Greg Mann; Hannes Ludewig; Philip Redpath; Marie Migaud; Nicholas J. Westwood; James H. Naismith. Derivatisable Cyanobactin Analogues: A Semisynthetic Approach. ChemBioChem 2015, 16, 2646 -2650.
AMA StyleEmilia Oueis, Catherine Adamson, Greg Mann, Hannes Ludewig, Philip Redpath, Marie Migaud, Nicholas J. Westwood, James H. Naismith. Derivatisable Cyanobactin Analogues: A Semisynthetic Approach. ChemBioChem. 2015; 16 (18):2646-2650.
Chicago/Turabian StyleEmilia Oueis; Catherine Adamson; Greg Mann; Hannes Ludewig; Philip Redpath; Marie Migaud; Nicholas J. Westwood; James H. Naismith. 2015. "Derivatisable Cyanobactin Analogues: A Semisynthetic Approach." ChemBioChem 16, no. 18: 2646-2650.
Virus replication efficiency is influenced by two conflicting factors, kinetics of the cellular interferon (IFN) response and induction of an antiviral state versus speed of virus replication and virus-induced inhibition of the IFN response. Disablement of a virus's capacity to circumvent the IFN response enables both basic research and various practical applications. However, such IFN-sensitive viruses can be difficult to grow to high-titer in cells that produce and respond to IFN. The current default option for growing IFN-sensitive viruses is restricted to a limited selection of cell-lines (e.g. Vero cells) that have lost their ability to produce IFN. This study demonstrates that supplementing tissue-culture medium with an IFN inhibitor provides a simple, effective and flexible approach to increase the growth of IFN-sensitive viruses in a cell-line of choice. We report that IFN inhibitors targeting components of the IFN response (TBK1, IKK2, JAK1) significantly increased virus replication. More specifically, the JAK1/2 inhibitor Ruxolitinib enhances the growth of viruses that are sensitive to IFN due to (i) loss of function of the viral IFN antagonist (due to mutation or species-specific constraints) or (ii) mutations/host cell constraints that slow virus spread such that it can be controlled by the IFN response. This was demonstrated for a variety of viruses, including, viruses with disabled IFN antagonists that represent live-attenuated vaccine candidates (Respiratory Syncytial Virus (RSV), Influenza Virus), traditionally attenuated vaccine strains (Measles, Mumps) and a slow-growing wild-type virus (RSV). In conclusion, supplementing tissue culture-medium with an IFN inhibitor to increase the growth of IFN-sensitive viruses in a cell-line of choice represents an approach, which is broadly applicable to research investigating the importance of the IFN response in controlling virus infections and has utility in a number of practical applications including vaccine and oncolytic virus production, virus diagnostics and techniques to isolate newly emerging viruses.
Claire E. Stewart; Richard Randall; Catherine Adamson. Inhibitors of the Interferon Response Enhance Virus Replication In Vitro. PLoS ONE 2014, 9, e112014 .
AMA StyleClaire E. Stewart, Richard Randall, Catherine Adamson. Inhibitors of the Interferon Response Enhance Virus Replication In Vitro. PLoS ONE. 2014; 9 (11):e112014.
Chicago/Turabian StyleClaire E. Stewart; Richard Randall; Catherine Adamson. 2014. "Inhibitors of the Interferon Response Enhance Virus Replication In Vitro." PLoS ONE 9, no. 11: e112014.
Protease-mediated maturation of HIV-1 virus particles is essential for virus infectivity. Maturation occurs concomitant with immature virus particle release and is mediated by the viral protease (PR), which sequentially cleaves the Gag and Gag-Pol polyproteins into mature protein domains. Maturation triggers a second assembly event that generates a condensed conical capsid core. The capsid core organizes the viral RNA genome and viral proteins to facilitate viral replication in the next round of infection. The fundamental role of proteolytic maturation in the generation of mature infectious particles has made it an attractive target for therapeutic intervention. Development of small molecules that target the PR active site has been highly successful and nine protease inhibitors (PIs) have been approved for clinical use. This paper provides an overview of their development and clinical use together with a discussion of problems associated with drug resistance. The second-half of the paper discusses a novel class of antiretroviral drug termed maturation inhibitors, which target cleavage sites in Gag not PR itself. The paper focuses on bevirimat (BVM) the first-in-class maturation inhibitor: its mechanism of action and the implications of naturally occurring polymorphisms that confer reduced susceptibility to BVM in phase II clinical trials.
Catherine Adamson. Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process. Molecular Biology International 2012, 2012, 1 -13.
AMA StyleCatherine Adamson. Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process. Molecular Biology International. 2012; 2012 ():1-13.
Chicago/Turabian StyleCatherine Adamson. 2012. "Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process." Molecular Biology International 2012, no. : 1-13.
Maturation of nascent virions, a key step in retroviral replication, involves cleavage of the Gag polyprotein by the viral protease into its matrix (MA), capsid (CA), and nucleocapsid (NC) components and their subsequent reorganization. Bevirimat (BVM) defines a new class of antiviral drugs termed maturation inhibitors. BVM acts by blocking the final cleavage event in Gag processing, the separation of CA from its C-terminal spacer peptide 1 (SP1). Prior evidence suggests that BVM binds to Gag assembled in immature virions, preventing the protease from accessing the CA-SP1 cleavage site. To investigate this hypothesis, we used cryo-electron tomography to examine the structures of (noninfectious) HIV-1 viral particles isolated from BVM-treated cells. We find that these particles contain an incomplete shell of density underlying the viral envelope, with a hexagonal honeycomb structure similar to the Gag lattice of immature HIV but lacking the innermost, NC-related, layer. We conclude that the shell represents a remnant of the immature Gag lattice that has been processed, except at the CA-SP1 sites, but has remained largely intact. We also compared BVM-treated particles with virions formed by the mutant CA5, in which cleavage between CA and SP1 is also blocked. Here, we find a thinner CA-related shell with no visible evidence of honeycomb organization, indicative of an altered conformation and further suggesting that binding of BVM stabilizes the immature lattice. In both cases, the observed failure to assemble mature capsids correlates with the loss of infectivity.
Paul W. Keller; Catherine Adamson; Bernard Heymann; Eric O. Freed; Alasdair C. Steven. HIV-1 Maturation Inhibitor Bevirimat Stabilizes the Immature Gag Lattice. Journal of Virology 2010, 85, 1420 -1428.
AMA StylePaul W. Keller, Catherine Adamson, Bernard Heymann, Eric O. Freed, Alasdair C. Steven. HIV-1 Maturation Inhibitor Bevirimat Stabilizes the Immature Gag Lattice. Journal of Virology. 2010; 85 (4):1420-1428.
Chicago/Turabian StylePaul W. Keller; Catherine Adamson; Bernard Heymann; Eric O. Freed; Alasdair C. Steven. 2010. "HIV-1 Maturation Inhibitor Bevirimat Stabilizes the Immature Gag Lattice." Journal of Virology 85, no. 4: 1420-1428.
The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. A patient's failure to respond correlated with baseline polymorphisms at SP1 residues 6-8.
Catherine S Adamson; Michael Sakalian; Karl Salzwedel; Eric O Freed. Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1maturation inhibitor bevirimat. Retrovirology 2010, 7, 36 -36.
AMA StyleCatherine S Adamson, Michael Sakalian, Karl Salzwedel, Eric O Freed. Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1maturation inhibitor bevirimat. Retrovirology. 2010; 7 (1):36-36.
Chicago/Turabian StyleCatherine S Adamson; Michael Sakalian; Karl Salzwedel; Eric O Freed. 2010. "Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1maturation inhibitor bevirimat." Retrovirology 7, no. 1: 36-36.
Considerable success has been achieved in the treatment of HIV-1 infection, and more than two-dozen antiretroviral drugs are available targeting several distinct steps in the viral replication cycle. However, resistance to these compounds emerges readily, even in the context of combination therapy. Drug toxicity, adverse drug–drug interactions, and accompanying poor patient adherence can also lead to treatment failure. These considerations make continued development of novel antiretroviral therapeutics necessary. In this article, we highlight a number of steps in the HIV-1 replication cycle that represent promising targets for drug discovery. These include lipid raft microdomains, the RNase H activity of the viral enzyme reverse transcriptase, uncoating of the viral core, host cell machinery involved in the integration of the viral DNA into host cell chromatin, virus assembly, maturation, and budding, and the functions of several viral accessory proteins. We discuss the relevant molecular and cell biology, and describe progress to date in developing inhibitors against these novel targets. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.
Catherine S. Adamson; Eric O. Freed. Novel approaches to inhibiting HIV-1 replication. Antiviral Research 2010, 85, 119 -141.
AMA StyleCatherine S. Adamson, Eric O. Freed. Novel approaches to inhibiting HIV-1 replication. Antiviral Research. 2010; 85 (1):119-141.
Chicago/Turabian StyleCatherine S. Adamson; Eric O. Freed. 2010. "Novel approaches to inhibiting HIV-1 replication." Antiviral Research 85, no. 1: 119-141.
Development of novel therapeutic targets against HIV-1 is a high research priority owing to the serious clinical consequences associated with acquisition of resistance to current antiretroviral drugs. The HIV-1 structural protein Gag represents a potential new therapeutic target as it plays a central role in virus particle production yet is not targeted by any of the antiretroviral drugs approved at present. The Gag polyprotein precursor multimerizes to form immature particles that bud from the infected cell. Concomitant with virus release, the Gag precursor undergoes proteolytic processing by the viral protease to generate the mature Gag proteins, which include capsid (CA). Once liberated from the Gag polyprotein precursor, CA molecules interact to reassemble into a condensed conical core, which organizes the viral RNA genome and several viral proteins to facilitate virus replication in the next round of infection. Correct Gag proteolytic processing and core assembly are therefore essential for virus infectivity. In this review, we discuss new strategies to inhibit maturation by targeting proteolytic cleavage sites in Gag or CA–CA interactions required for core formation. The identification and development of lead maturation inhibitors are highlighted.
Catherine Adamson; Karl Salzwedel; Eric O. Freed. Virus maturation as a new HIV-1 therapeutic target. Expert Opinion on Therapeutic Targets 2009, 13, 895 -908.
AMA StyleCatherine Adamson, Karl Salzwedel, Eric O. Freed. Virus maturation as a new HIV-1 therapeutic target. Expert Opinion on Therapeutic Targets. 2009; 13 (8):895-908.
Chicago/Turabian StyleCatherine Adamson; Karl Salzwedel; Eric O. Freed. 2009. "Virus maturation as a new HIV-1 therapeutic target." Expert Opinion on Therapeutic Targets 13, no. 8: 895-908.
The maturation inhibitor bevirimat [3-O-(3′,3′dimethysuccinyl)betulinic acid; BVM; also known as PA-457 or DSB] potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking protease (PR)-mediated cleavage at the junction between capsid (CA) and spacer peptide 1 (SP1) in Gag. We previously isolated a panel of single-amino-acid substitutions that confer resistance to BVM in vitro (C. S. Adamson, S. D. Ablan, I. Boeras, R. Goila-Gaur, F. Soheilian, K. Nagashima, F. Li, K. Salzwedel, M. Sakalian, C. T. Wild, and E. O. Freed, J. Virol. 80:10957-10971, 2006). The BVM resistance mutations cluster at or near the CA-SP1 cleavage site. Because BVM likely will be used clinically in patients harboring viruses resistant to PR inhibitors (PIs), in this study we evaluated the interplay between a PI-resistant (PIR) PR and the BVM resistance mutations in Gag. As expected, the PIR mutations had no effect on inhibition by BVM; however, we observed general processing defects and a slight delay in viral replication in Jurkat T cells associated with the PIR mutations, even in the absence of compound. When combined, most BVM resistance and PIR mutations acted additively to impair viral replication, particularly in the presence of BVM. The BVM-resistant mutant SP1-A1V was an exception, as it supported robust replication in the context of either wild-type (WT) or PIR PR, even at high BVM concentrations. Significantly, the emergence of BVM resistance was delayed in the context of the PIR PR, and the SP1-A1V mutation was acquired most frequently with either WT or PIR PR. These results suggest that resistance to BVM is less likely to emerge in patients who have failed PIs than in patients who are PI naïve. We predict that the SP1-A1V substitution is the most likely to emerge in vivo, as this mutant replicates robustly independently of PR mutations or BVM. These findings offer insights into the effect of PIR mutations on the evolution of BVM resistance in PI-experienced patients.
Catherine S. Adamson; Kayoko Waki; Sherimay D. Ablan; Karl Salzwedel; Eric O. Freed. Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457). Journal of Virology 2009, 83, 4884 -4894.
AMA StyleCatherine S. Adamson, Kayoko Waki, Sherimay D. Ablan, Karl Salzwedel, Eric O. Freed. Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457). Journal of Virology. 2009; 83 (10):4884-4894.
Chicago/Turabian StyleCatherine S. Adamson; Kayoko Waki; Sherimay D. Ablan; Karl Salzwedel; Eric O. Freed. 2009. "Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457)." Journal of Virology 83, no. 10: 4884-4894.
More than twenty-five years after its discovery, HIV-1 remains one of the world’s most formidable and destructive pathogens. Several classes of anti-HIV-1 agents are currently in widespread clinical use in developed nations; however, viral resistance to these drugs limits their effectiveness in a growing number of patients. It is therefore imperative that novel drugs be developed. Recent advances in the fields of HIV-1 molecular virology and cell biology have revealed possible new targets for drug discovery. The current status of antiretroviral therapy and some of the promising new targets against which novel antiviral agents could be developed are discussed.
Catherine S. Adamson; Eric O. Freed. Anti-HIV-1 Therapeutics: From FDA-approved Drugs to Hypothetical Future Targets. Molecular Interventions 2009, 9, 70 -74.
AMA StyleCatherine S. Adamson, Eric O. Freed. Anti-HIV-1 Therapeutics: From FDA-approved Drugs to Hypothetical Future Targets. Molecular Interventions. 2009; 9 (2):70-74.
Chicago/Turabian StyleCatherine S. Adamson; Eric O. Freed. 2009. "Anti-HIV-1 Therapeutics: From FDA-approved Drugs to Hypothetical Future Targets." Molecular Interventions 9, no. 2: 70-74.
Recent failures in efforts to develop an effective vaccine against HIV-1 infection have emphasized the importance of antiretroviral therapy in treating HIV-1-infected patients. Thus far, inhibitors of two viral enzymes, reverse transcriptase and protease, have had a profoundly positive impact on the survival of HIV-1-infected patients. However, new inhibitors that act at diverse steps in the viral replication cycle are urgently needed because of the development of resistance to currently available antiretrovirals. This review summarizes recent progress in antiretroviral drug discovery and development by specifically focusing on novel inhibitors of three phases of replication: viral entry, integration of the viral DNA into the host cell genome and virus particle maturation.
Catherine Adamson; Eric O. Freed. Recent progress in antiretrovirals – lessons from resistance. Drug Discovery Today 2008, 13, 424 -432.
AMA StyleCatherine Adamson, Eric O. Freed. Recent progress in antiretrovirals – lessons from resistance. Drug Discovery Today. 2008; 13 (9-10):424-432.
Chicago/Turabian StyleCatherine Adamson; Eric O. Freed. 2008. "Recent progress in antiretrovirals – lessons from resistance." Drug Discovery Today 13, no. 9-10: 424-432.
Infection of domestic cats with feline immunodeficiency virus (FIV) is an important model system for studying human immunodeficiency virus type 1 (HIV-1) infection due to numerous similarities in pathogenesis induced by these two lentiviruses. However, many molecular aspects of FIV replication remain poorly understood. It is well established that retroviruses use short peptide motifs in Gag, known as late domains, to usurp cellular endosomal sorting machinery and promote virus release from infected cells. For example, the Pro-Thr/Ser-Ala-Pro [P(T/S)AP] motif of HIV-1 Gag interacts directly with Tsg101, a component of the endosomal sorting complex required for transport I (ESCRT-I). A Tyr-Pro-Asp-Leu (YPDL) motif in equine infectious anemia virus (EIAV), and a related sequence in HIV-1, bind the endosomal sorting factor Alix. In this study we sought to identify and characterize FIV late domain(s) and elucidate cellular machinery involved in FIV release. We determined that mutagenesis of a PSAP motif in FIV Gag, small interfering RNA-mediated knockdown of Tsg101 expression, and overexpression of a P(T/S)AP-binding fragment of Tsg101 (TSG-5′) each inhibited FIV release. We also observed direct binding of FIV Gag peptides to Tsg101. In contrast, mutagenesis of a potential Alix-binding motif in FIV Gag did not affect FIV release. Similarly, expression of the HIV-1/EIAV Gag-binding domain of Alix (Alix-V) did not disrupt FIV budding, and FIV Gag peptides showed no affinity for Alix-V. Our data demonstrate that FIV relies predominantly on a Tsg101-binding PSAP motif in the C terminus of Gag to promote virus release in HeLa cells, and this budding mechanism is highly conserved in feline cells.
Benjamin G. Luttge; Miranda Shehu-Xhilaga; Dimiter G. Demirov; Catherine S. Adamson; Ferri Soheilian; Kunio Nagashima; Andrew G. Stephen; Robert J. Fisher; Eric O. Freed. Molecular Characterization of Feline Immunodeficiency Virus Budding. Journal of Virology 2008, 82, 2106 -2119.
AMA StyleBenjamin G. Luttge, Miranda Shehu-Xhilaga, Dimiter G. Demirov, Catherine S. Adamson, Ferri Soheilian, Kunio Nagashima, Andrew G. Stephen, Robert J. Fisher, Eric O. Freed. Molecular Characterization of Feline Immunodeficiency Virus Budding. Journal of Virology. 2008; 82 (5):2106-2119.
Chicago/Turabian StyleBenjamin G. Luttge; Miranda Shehu-Xhilaga; Dimiter G. Demirov; Catherine S. Adamson; Ferri Soheilian; Kunio Nagashima; Andrew G. Stephen; Robert J. Fisher; Eric O. Freed. 2008. "Molecular Characterization of Feline Immunodeficiency Virus Budding." Journal of Virology 82, no. 5: 2106-2119.
A well defined structure is available for the carboxyl half of the cellular prion protein (PrP(c)), while the structure of the amino terminal half of the molecule remains ill defined. The unstructured nature of the polypeptide has meant that relatively few of the many antibodies generated against PrP(c) recognise this region. To circumvent this problem, we have used a previously characterised and well expressed fragment derived from the amino terminus of PrP(c) as bait for panning a single chain antibody phage (scFv-P) library. Using this approach, we identified and characterised 1 predominant and 3 additional scFv-Ps that contained different V(H) and V(L) sequences and that bound specifically to the PrP(c) target. Epitope mapping revealed that all scFv-Ps recognised linear epitopes between PrP(c) residues 76 and 156. When compared with existing monoclonal antibodies (MAb), the binding of the scFvs was significantly different in that high level binding was evident on truncated forms of PrP(c) that reacted poorly or not at all with several pre-existing MAbs. These data suggest that the isolated scFv-Ps bind to novel epitopes within the amino-central region of PrP(c). In addition, the binding of MAbs to known linear epitopes within PrP(c) depends strongly on the endpoints of the target PrP(c) fragment used.
Catherine S. Adamson; Yongxiu Yao; Snezana Vasiljevic; Man-Sun Sy; Junyuan Ren; Ian M. Jones. Novel single chain antibodies to the prion protein identified by phage display. Virology 2007, 358, 166 -177.
AMA StyleCatherine S. Adamson, Yongxiu Yao, Snezana Vasiljevic, Man-Sun Sy, Junyuan Ren, Ian M. Jones. Novel single chain antibodies to the prion protein identified by phage display. Virology. 2007; 358 (1):166-177.
Chicago/Turabian StyleCatherine S. Adamson; Yongxiu Yao; Snezana Vasiljevic; Man-Sun Sy; Junyuan Ren; Ian M. Jones. 2007. "Novel single chain antibodies to the prion protein identified by phage display." Virology 358, no. 1: 166-177.
Catherine S. Adamson; Eric O. Freed. Human Immunodeficiency Virus Type 1 Assembly, Release, and Maturation. Studies in Surface Science and Catalysis 2007, 55, 347 -387.
AMA StyleCatherine S. Adamson, Eric O. Freed. Human Immunodeficiency Virus Type 1 Assembly, Release, and Maturation. Studies in Surface Science and Catalysis. 2007; 55 ():347-387.
Chicago/Turabian StyleCatherine S. Adamson; Eric O. Freed. 2007. "Human Immunodeficiency Virus Type 1 Assembly, Release, and Maturation." Studies in Surface Science and Catalysis 55, no. : 347-387.
3- O -(3′,3′-dimethylsuccinyl)betulinic acid (PA-457 or bevirimat) potently inhibits human immunodeficiency virus type 1 (HIV-1) maturation by blocking a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C terminus of capsid (CA). To gain insights into the mechanism(s) by which HIV-1 could evolve resistance to PA-457 and to evaluate the likelihood of such resistance arising in PA-457-treated patients, we sought to identify and characterize a broad spectrum of HIV-1 variants capable of conferring resistance to this compound. Numerous independent rounds of selection repeatedly identified six single-amino-acid substitutions that independently confer PA-457 resistance: three at or near the C terminus of CA (CA-H226Y, -L231F, and -L231M) and three at the first and third residues of SP1 (SP1-A1V, -A3T, and -A3V). We determined that mutations CA-H226Y, CA-L231F, CA-L231M, and SP1-A1V do not impose a significant replication defect on HIV-1 in culture. In contrast, mutations SP1-A3V and -A3T severely impaired virus replication and inhibited virion core condensation. The replication defect imposed by SP1-A3V was reversed by a second-site compensatory mutation in CA (CA-G225S). Intriguingly, high concentrations of PA-457 enhanced the maturation of SP1 residue 3 mutants. The different phenotypes associated with mutations that confer PA-457 resistance suggest the existence of multiple mechanisms by which HIV-1 can evolve resistance to this maturation inhibitor. These findings have implications for the ongoing development of PA-457 to treat HIV-1 infection in vivo.
Catherine S. Adamson; Sherimay D. Ablan; Ioana Boeras; Ritu Goila-Gaur; Ferri Soheilian; Kunio Nagashima; Feng Li; Karl Salzwedel; Michael Sakalian; Carl T. Wild; Eric O. Freed. In Vitro Resistance to the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PA-457 (Bevirimat). Journal of Virology 2006, 80, 10957 -10971.
AMA StyleCatherine S. Adamson, Sherimay D. Ablan, Ioana Boeras, Ritu Goila-Gaur, Ferri Soheilian, Kunio Nagashima, Feng Li, Karl Salzwedel, Michael Sakalian, Carl T. Wild, Eric O. Freed. In Vitro Resistance to the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PA-457 (Bevirimat). Journal of Virology. 2006; 80 (22):10957-10971.
Chicago/Turabian StyleCatherine S. Adamson; Sherimay D. Ablan; Ioana Boeras; Ritu Goila-Gaur; Ferri Soheilian; Kunio Nagashima; Feng Li; Karl Salzwedel; Michael Sakalian; Carl T. Wild; Eric O. Freed. 2006. "In Vitro Resistance to the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PA-457 (Bevirimat)." Journal of Virology 80, no. 22: 10957-10971.