Peptide Triazole Inhibitors of HIV-1: Hijackers of Env Metastability

With 1.5 million new infections and 690,000 AIDS-related deaths globally each year, HIV- 1 remains a pathogen of significant public health concern. Although a wide array of effective antiretroviral drugs have been discovered, these largely target intracellular stages of the viral infectious cycle, and inhibitors that act at or before the point of viral entry still require further advancement. A unique class of HIV-1 entry inhibitors, called peptide triazoles (PTs), has been developed, which irreversibly inactivates Env trimers by exploiting the protein structure's innate metastable nature. PTs, and a related group of inhibitors called peptide triazole thiols (PTTs), are peptide compounds that dually engage the CD4 receptor and coreceptor binding sites of Env's gp120 subunit. This triggers dramatic conformational rearrangements of Env, including the shedding of gp120 (PTs and PTTs) and lytic transformation of the gp41 subunit to a post-fusion-like arrangement (PTTs). Due to the nature of their dual receptor site engagement, PT/PTT-induced conformational changes may elucidate mechanisms behind the native fusion program of Env trimers following receptor and coreceptor engagement, including the role of thiols in fusion. In addition to inactivating Env, PTT-induced structural transformation enhances the exposure of important and conserved neutralizable regions of gp41, such as the membrane proximal external region (MPER). PTT-transformed Env could present an intriguing potential vaccine immunogen prototype. In this review, we discuss the origins of the PT class of peptide inhibitors, our current understanding of PT/PTT-induced structural perturbations and viral inhibition, and prospects for using these antagonists for investigating Env structural mechanisms and for vaccine development.