Mutational analysis identifies conserved amino acids necessary for the infection of human polyomavirus species JCPyV and BKPyV
Embargo Date
2026-11-24
OA Version
Citation
Abstract
Recent advances have led to the recognition that humans harbor approximately thirteen polyomavirus species, a dramatic increase from the two that were known prior to 2007. Polyomaviruses are non-enveloped double-stranded (ds) DNA viruses that establish lifelong infections in human populations. Infections from these viruses are clinically asymptomatic in healthy individuals; however, they may become pathogenic in people who are immunocompromised. Therefore, there is an increasing unmet medical need for therapeutics capable of preventing infection from these viruses. The goal of the current project was to aid in the design of capsid inhibitors which would prevent infection from multiple human polyomaviruses. To assess the feasibility of designing a pan-capsid inhibitor, we compared structural data from the two most common polyomaviruses, BK virus (BKPyV; human polyomavirus 1) and JC virus (JCPyV; human polyomavirus 2), to identify highly conserved regions. An 11 amino acid motif (WMLPLLLGLYG) in the structural viral protein 2 (VP2) and 3 (VP3) sequences of JCV and BKV which binds to structural viral protein 1 (VP1) is 100% conserved. To test whether targeting this region would disrupt the interaction of VP2 and VP3 with the VP1 pentamer, we made a series of homologous VP1 mutations in the viral capsids of JCV and BKV and genetically validated their effect on VP1 pentamer formation, viral capsid protein composition, and cellular infectivity. Our results demonstrate that targeting this binding region is effective at completely abolishing cellular infectivity of these viruses. Overall, this series of experiments identifies a promising hotspot, conserved amongst the two most common polyomaviruses, with which to design next generation capsid inhibitors to prevent disease.
Description
2025
License
Attribution-NonCommercial-ShareAlike 4.0 International