HIV Capsid Inhibitors Beyond PF74

Abstract

Human immunodeficiency virus (HIV) capsid plays important roles at multiple stages of viral replication. At the initial stages, controlled uncoating (disassembly) of the capsid ensures efficient reverse transcription of the single-stranded RNA genome, into the double-stranded DNA. Whereas at later stages, a proper assembly of capsid ensures the formation of a mature infectious virus particle. Hence, the inhibition of capsid assembly and/or disassembly has been recognized as a potential therapeutic strategy, and several capsid inhibitors have been reported. Of these, PF-3450074 (PF74) has been extensively studied. Recently reported GS-CA inhibitors (GS-CA1 and GS-6207), have shown a strong potential and appear to contain a PF74 scaffold. The location of resistance mutations and the results of structural studies further suggest that GS-CA compounds and PF74 share the same binding pocket, which is located between capsid monomers. Additionally, phenylalanine derivatives containing the PF74 scaffold show slightly enhanced capsid inhibiting activity. A comparison of capsid structures in complex with host factors and PF74, reveals the presence of common chemical entities at topologically equivalent positions. Here we present the status of capsid inhibitors that contain PF74 scaffolds and propose that the PF74 scaffold may be used to develop strong and safe capsid inhibitors.

PF74 and Its Novel Derivatives Stabilize Hexameric Lattice of HIV-1 Mature-Like Particles

“…To analyze the effects of the PF74 derivatives on the assembly of mature-like HIV-1 particles, we mixed the tested inhibitors with HIV-1 CANC protein and, following a one hour incubation, the assembly reaction was initiated by tqON addition. Next, Exonuclease I To improve the poor therapeutic qualities and poor metabolic stability [55], several efforts to modify PF74 were reported [45,46,55,56]. In this work, we report several modifications of the indole and linker part of the PF74 molecule.…”

Identification of a Potential Inhibitor of the FIV p24 Capsid Protein and Characterization of Its Binding Site

“…These compounds do not inhibit FIV replication in vitro 53 , but the molecular docking of 696 demonstrates that it interacts with FIV p24 similar to the interaction of PF74 with HIV-1 p24. It is interesting to note that these HIV-1 inhibitors have been demonstrated to target the p24:p24 interfaces in HIV-1 p24 capsomers 41,49,52 .…”

Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

“…As this dimerization is necessary for TIM function, our data suggest that our compounds could inhibit TIM by modifying or blocking the interface of the dimer. Inhibitors of protein:protein interactions have been sought for more than thirty years 19 and although our compounds are small compared to the TIM interface, previous examples of small molecules inhibiting protein assembly have been described 30 . Moreover, in our case, as the catalytic site is at the dimeric interface, a disturbance of the topology of the interface, even if not leading to the disassembly of the dimer, could be sufficient to inhibit TIM function.…”