Reviewing HIV-1 Gag Mutations in Protease Inhibitors Resistance: Insights for Possible Novel Gag Inhibitor Designs

Abstract

HIV protease inhibitors against the viral protease are often hampered by drug resistance mutations in protease and in the viral substrate Gag. To overcome this drug resistance and inhibit viral maturation, targeting Gag alongside protease rather than targeting protease alone may be more efficient. In order to successfully inhibit Gag, understanding of its drug resistance mutations and the elicited structural changes on protease binding needs to be investigated. While mutations on Gag have already been mapped to protease inhibitor resistance, there remain many mutations, particularly the non-cleavage mutations, that are not characterized. Through structural studies to unravel how Gag mutations contributes to protease drug resistance synergistically, it is thus possible to glean insights to design novel Gag inhibitors. In this review, we discuss the structural role of both novel and previously reported Gag mutations in PI resistance, and how new Gag inhibitors can be designed.

The Determination of HIV-1 RT Mutation Rate, Its Possible Allosteric Effects, and Its Implications on Drug Resistance

“…For a better study of HIV-1 RT, the mutation positions are important to provide mechanistic insights to the development of drug resistance [76]. The well-established mutation rate of HIV-1 RT is performed on lacZα [39][40][41][42][43][44][45]48,58,77], resulting in a gap of knowledge regarding how HIV-1 genes are mutated by RT.…”

“…For example, the M184V resistance mutation in HIV-1 RT is known to increase fidelity, impair viral fitness, and increase hyper-sensitization to NRTIs (such as amprenavir and efavirenz) [99]. Thus, it is possible to leverage on such features alongside structural understanding [76] to utilize combinatorial therapies to target the active site, using existing inhibitors to select for the mutation alongside other inhibitors to limit the escape mutations.…”

In Vivo Emergence of a Novel Protease Inhibitor Resistance Signature in HIV-1 Matrix

“…A number of studies have attempted to establish Gag as a target. The design and development of drugs that target Gag could be approached in four broad ways, as reviewed by Su and colleagues ( 41 ). The first approach would involve screening and targeting of druggable allosteric sites present in Gag.…”

“…The third approach is the use of synergistic drugs to target multiple sites by chemically joining different potential Gag inhibitors to function as dual or triple inhibitors. The fourth approach is to design inhibitors to disrupt the conformational transition of Gag during viral maturation ( 41 ).…”

“…The use of a small-molecule approach was also adopted by Machara et al and led to the identification of two arylquinazolines which inhibited HIV-1 capsid assembly by binding to the C-terminal domain of capsid and blocking viral replication ( 44 ). Additionally, inhibitors could be synthesized to destabilize Gag assembly, thus slowing the viral maturation process ( 41 ).…”