Over the last few decades, concepts of protein intrinsic disorder have been implicated in different biological processes. Recent studies have suggested that intrinsically disordered proteins (IDPs) provide structural plasticity and functional diversity to viral proteins that are involved in rapid replication and immune evasion in host cells. In case of Zika virus, the roles of protein intrinsic disorder in mechanisms of pathogenesis are not completely understood. In this study, we have analyzed the prevalence of intrinsic disorder in Zika virus proteome (strain MR 766). Our analyses revealed that Zika virus polyprotein is enriched with intrinsically disordered protein regions (IDPRs) and this finding is consistent with previous reports on the involvement of IDPs in shell formation and virulence of the Flaviviridae family. We found abundant IDPRs in Capsid, NS2B, NS3, NS4A, and NS5 proteins that are involved in mature particle formation and replication. In our view, the intrinsic disorder-focused analysis of ZIKV proteins could be important for the development of disorder-based drugs.

The concept of protein intrinsic disorder has taken the driving seat to understand regulatory proteins in general. Reports suggest that in mammals nearly 75% of signalling proteins contain long disordered regions with greater than 30 amino acid residues. Therefore, intrinsically disordered proteins (IDPs) have been implicated in several human diseases and should be considered as potential novel drug targets. Moreover, intrinsic disorder provides a huge multifunctional capability to hub proteins such as c-Myc and p53. c-Myc is the hot spot for understanding and developing therapeutics against cancers and cancer stem cells. Our past understanding is mainly based on in vitro and in vivo experiments conducted using c-Myc as whole protein. Using the reductionist approach, c-Myc oncoprotein has been divided into structured and disordered domains. A wealth of data is available dealing with the structured perspectives of c-Myc, but understanding c-Myc in terms of disordered domains has just begun. Disorderness provides enormous flexibility to proteins in general for binding to numerous partners. Here, we have reviewed the current progress on understanding c-Myc using the emerging concept of IDPs.

Chikungunya virus (CHIKV) infection is one of the major public health concerns, leading thousands of cases every year in rural as well as urban regions of several countries worldwide, few to mention are India, Philippines, Indonesia, and also in American countries. The structural and non-structural proteins of CHIKV are structurally and functionally similar to other alphaviruses such as Sindbis virus, Venezuelan Equine Encephalitis virus. The precursor protein of non-structural proteins is cleaved by proteolytic activity of non-structural protein (nsp2). This multifunctional nsp2 carry out nucleoside-triphosphatase (NTPase) and RNA helicase activity at its N-terminal and protease activity at C-terminal that makes it primarily a drug target to inhibit CHIKV replication. Until the current date, no suitable treatment for chikungunya infection is available. The introduction of a new drug into the market is a lengthy process, therefore, drug repurposing is now familiar approach that cut off the time and cost of drug discovery. In this study, we have implemented this approach with Food and Drug Administration (FDA) approved drugs and known cysteine protease inhibitors against CHIKV nsp2 protease using structure-based drug discovery. Our extensive docking and molecular dynamics simulations studies leads to two best interacting compounds, Ribostamycin sulfate and E-64, with utmost stable complexes at active site of nsp2 protease. Therefore, these compounds could be suitable for inhibiting CHIKV protease activity, and ultimately the viral replication.

Zika virus (ZIKV) is unique among orthoflaviviruses in its vertical transmission capacity in humans, yet the underlying mechanisms remain incompletely understood. Here, we show that ZIKV induces tunneling nanotubes (TNTs) in placental trophoblasts which facilitate transfer of viral particles, proteins, mitochondria, and RNA to neighboring uninfected cells. TNT formation is driven exclusively via ZIKV non-structural protein 1 (NS1). Specifically, the N-terminal 1-50 amino acids of membrane-bound ZIKV NS1 are necessary for triggering TNT formation in host cells. Trophoblasts infected with TNT-deficient ZIKV^ΔTNT mutant virus elicited a robust antiviral IFN-λ 1/2/3 response relative to WT ZIKV, suggesting TNT-mediated trafficking allows ZIKV cell-to-cell transmission camouflaged from host defenses. Using affinity purification-mass spectrometry of cells expressing wild-type NS1 or non-TNT forming NS1, we found mitochondrial proteins are dominant NS1-interacting partners. We demonstrate that ZIKV infection or NS1 expression induces elevated mitochondria levels in trophoblasts and that mitochondria are siphoned via TNTs from healthy to ZIKV-infected cells. Together our findings identify a stealth mechanism that ZIKV employs for intercellular spread among placental trophoblasts, evasion of antiviral interferon response, and the hijacking of mitochondria to augment its propagation and survival and offers a basis for novel therapeutic developments targeting these interactions to limit ZIKV dissemination.