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- W2913591718 abstract "Complex enveloped viruses have an intriguingly robust ability to assemble, package, and release viral materials from host cells as virions to spread infection. Human immunodeficiency virus type-1 (HIV-1) is one paradigmatic example, and a plethora of small molecule drugs have been developed to disrupt the many stages of the viral lifecycle. The current paradigm involves competitive inhibition of viral enzymes and receptors. However, drug-resistance due to genetic polymorphism remains a key challenge. Instead, an alternative strategy is to target the main structural polyprotein known as Gag, which coordinates several steps of viral morphogenesis and conserves over 70% of its residues amongst subtypes. A class of drugs known as capsid inhibitors, e.g., PF-74 from Pfizer and GS-CA1 from Gilead Sciences, have recently emerged with this aim in mind. Nonetheless, their molecular mechanisms of action have remained elusive. For example, different studies involving PF-74 suggest many potential mechanisms, which include the drug destabilizing viral cores during infection, abrogating nuclear transport, over-stabilizing cores to prevent reverse transcription, and preventing core assembly. In this talk, we will describe the use of large-scale coarse-grained (CG) molecular dynamics simulations to investigate the putative mechanisms of capsid inhibitors, in which we explore the complete assembly of capsid proteins during viral maturation and their disassembly during uncoating. Our simulations broadly suggest that capsid inhibitors accelerate capsid assembly, thereby undermining this necessarily-controlled process. As a result, several mechanisms of action are expressed, including malformed core formation and spontaneous core uncoating. Taken together, our results provide fundamental biophysical understanding into supramolecular protein assembly and elucidate a broad-spectrum biomedical strategy to combat viral infection." @default.
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- W2913591718 date "2019-02-01" @default.
- W2913591718 modified "2023-10-14" @default.
- W2913591718 title "The Mechanism of Action for Drugs that Undermine HIV-1 Viral Capsid Formation and Activity: Insights from Large-Scale Coarse-Grained Simulations" @default.
- W2913591718 doi "https://doi.org/10.1016/j.bpj.2018.11.378" @default.
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