HIV GAG Inhibitors

Chemical inhibitors of the HIV GAG polyprotein function through various mechanisms to interrupt the HIV life cycle by targeting different stages of GAG polyprotein processing and assembly. Bevirimat, also known as PA-457, operates by binding directly to the GAG polyprotein, specifically targeting its maturation process. By doing so, it hampers the cleavage of GAG into functional viral proteins, which are imperative for viral assembly and maturation. Another compound, PF-46396, exhibits its inhibitory action in an allosteric fashion, attaching to the GAG polyprotein and disrupting the proper folding and processing necessary for viral particle assembly and release. Similarly, BI 224436 binds to the hexameric interface of the HIV GAG polyprotein, thereby interfering with capsid assembly and generating non-infectious viral particles.

Expanding on the range of inhibitory strategies, L-731988 disrupts the interaction between the GAG polyprotein and crucial cellular factors, such as Tsg101 which is part of the ESCRT-I complex, impeding the release of viral particles. GSK3532795 adds to the arsenal by blocking the interaction of the GAG polyprotein with necessary host cell factors, interfering notably with the late stages of Gag processing and particle maturation. GSK1265744, known as Cabotegravir, while primarily an integrase inhibitor, indirectly limits the availability of GAG for new virion assembly by preventing the integration of viral DNA into the host genome. Darunavir, a protease inhibitor, indirectly precludes the maturation of the GAG polyprotein by inhibiting its cleavage into mature, functional proteins. Tenofovir, a nucleotide reverse transcriptase inhibitor, prevents HIV replication and consequently the production of GAG polyproteins in newly infected cells. Raltegravir blocks the integrase enzyme, essential for integrating viral DNA into host chromosomes, thus affecting the synthesis of viral proteins including GAG. Finally, BMS-626529 interrupts the GAG polyprotein production process by blocking the virus's attachment to CD4+ T cells, thereby preventing the entry and replication of the virus that is necessary for the production of GAG in newly infected cells.