Abstract
HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents an appealing antiviral target. Several CA-targeting small molecules of various chemotypes have been studied, but the peptidomimetic PF74 has drawn particular interest due to its potent antiviral activity, well-characterized binding mode, and unique mechanism of action. Importantly, PF74 competes against important host factors for binding, conferring highly desirable antiviral phenotypes. However, further development of PF74 is hindered by its prohibitively poor metabolic stability, which necessitates the search for structurally novel and metabolically stable chemotypes. We have conducted a pharmacophore-based shape similarity search for compounds mimicking PF74. We report herein the analog synthesis and structure-activity relationship (SAR) of two hits from the search, and a third hit designed via molecular hybridization. All analogs were characterized for their effect on CA hexamer stability, antiviral activity, and cytotoxicity. These assays identified three active compounds that moderately stabilize CA hexamer and inhibit HIV-1. The most potent analog (10) inhibited HIV-1 comparably to PF74 but demonstrated drastically improved metabolic stability in liver microsomes (31 min vs. 0.7 min t1/2). Collectively, the current studies identified a structurally novel and metabolically stable PF74-like chemotype for targeting HIV-1 CA.
Highlights
Human immunodeficiency virus 1 (HIV-1) encodes a Gag polyprotein which contains multiple protein domains for viral assembly and release: matrix (p17 MA), capsid (p24 capsid protein (CA)), nucleocapsid (p7NC), p6 and spacer peptides Sp1 and Sp2 [1]
Interactions drive the assembly and disassembly of viral capsid, and capsid core stability is important for reverse transcription, nuclear entry, and cloaking of the viral DNA product from host nucleic acid sensing
We report the analog synthesis and structure-activity relationship (SAR) on all three hits
Summary
Human immunodeficiency virus 1 (HIV-1) encodes a Gag polyprotein which contains multiple protein domains for viral assembly and release: matrix (p17 MA), capsid (p24 CA), nucleocapsid (p7NC), p6 and spacer peptides Sp1 and Sp2 [1]. Gag polyproteins assemble to form the immature viral capsid core, which upon protease cleavage rearranges into a fullerene-shaped mature capsid core [2]. CA-CA interactions drive the assembly and disassembly of viral capsid, and capsid core stability is important for reverse transcription, nuclear entry, and cloaking of the viral DNA product from host nucleic acid sensing. (NUP153, NUP358), MxB [19,20], and Cyclophilin A (CypA) [21,22,23] These interactions enable early viral replication steps, including uncoating, cytoplasmic trafficking, reverse transcription, nuclear transport, site of integration, and the evasion of innate immunity [24]. CA-targeting small molecules could confer both early and late stage antiviral phenotypes by perturbing the stability of viral capsid core and interfering with important CA-host interactions
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