Abstract
A major structural retroviral protein, capsid protein (CA), is able to oligomerize into two different hexameric lattices, which makes this protein a key component for both the early and late stages of HIV-1 replication. During the late stage, the CA protein, as part of the Gag polyprotein precursor, facilitates protein–protein interactions that lead to the assembly of immature particles. Following protease activation and Gag polyprotein processing, CA also drives the assembly of the mature viral core. In the early stage of infection, the role of the CA protein is distinct. It controls the disassembly of the mature CA hexameric lattice i.e., uncoating, which is critical for the reverse transcription of the single-stranded RNA genome into double stranded DNA. These properties make CA a very attractive target for small molecule functioning as inhibitors of HIV-1 particle assembly and/or disassembly. Of these, inhibitors containing the PF74 scaffold have been extensively studied. In this study, we reported a series of modifications of the PF74 molecule and its characterization through a combination of biochemical and structural approaches. Our data supported the hypothesis that PF74 stabilizes the mature HIV-1 CA hexameric lattice. We identified derivatives with a higher in vitro stabilization activity in comparison to the original PF74 molecule.
Highlights
Capsid protein (CA) is the main structural protein of retroviral particles
To quantify the designed effect of PF74 the stability of the enhance the inhibiting capability of PF74, we and derivatives synthesizedon a series of modified viral capsid, we used a combination of in substituent vitro, cell-based, and NMR structural assays
The capability to interact with the PF74 binding sites of capsid protein (CA) was tested in silico by the the hypothesis that the mechanism of USA)
Summary
Capsid protein (CA) is the main structural protein of retroviral particles. CA consists of two helical domains, the N-terminal (CA-NTD) and C-terminal (CA-CTD) domains, which are connected by a short linker. Later on, following retroviral protease activation, the Gag polyprotein is processed to individual structural proteins and released as CA molecules re-assembled into mature hexameric lattice that form a viral core or capsid. Molecules 2020, 25, 1895 several openings (gaps) in the structure [5], the properly assembled mature hexameric lattice can form fully closed fullerene or multilayered structures [1] This is enabled by the accommodation of twelve pentamers in the hexameric structure of mature retroviral cores [1,6,7,8,9]. Uncoating is a poorly understood post-entry event in the early stage of the retroviral life cycle, comprising controlled disassembly of the core upon entering the cytoplasm.
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