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Structure-guided design of BK/JC virus capsid targeting antivirals

BK and JC viruses are closely related members of the polyomavirus family that latently infect 70-90% of humans and cause fatal clinical complications in immunocompromised patients (kidney failure and brain demyelination). There are no effective drugs to treat these infections. The lack of conventional, enzymatic antiviral targets such as proteases or integrases makes any development challeging. The small genome of polyomaviruses encodes two major proteins, VP1 (the main capsid protein) and large T-antigen. Recently capsid assembly inhibitors have entered clinical development for HIV, hepatitis B and C viruses. Here we propose a concerted structure-based effort to rationally design inhibitors of BK/JC virus assembly. We conducted an extensive X-ray crystallography basedscreen with over 1000 drug-like fragments tested for their binding to BK VP1 pentamers. This resulted in the identification of novel binding sites, including a specific induced pocket located at the interface of two pentamers. Pre-existing genetic and in vivo studies suggest that this site is not only relevant for the capsid assembly but also critical for viral packaging. Here we will utilize the results of our fragment screening towards developing the pharmacophore of this druggable pocket as well as grow and merge the fragment hits towards developing higher affinity lead compounds. These improved compounds will be evaluated through X-ray analysis and binding affinity measurements, as well as tested in a func

Date:1 Jan 2018 →  31 Dec 2021
Keywords:BK virus, Antivirals, JC virus
Disciplines:Other biological sciences, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences