Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41

Abstract

Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus serving as key targets for the development of HIV-1 entry inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV entry inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV entry inhibitor candidates and further predicted the future trend of HIV entry inhibitor development.

HIV‐1 Entry Inhibitors: A Review of Experimental and Computational Studies

“…The reason is that the CD4 binding site of gp120 is more accessible in comparison with gp41 hydrophobic pocket, which is exposed after the attachment of gp120 to CD4 just for a few minutes. However, gp41 inhibitors, targeting the hydrophobic pocket, have broader spectrum of activity against different HIV strains, since this part of gp41 is more conserved compared to CD4‐binding site in gp120 …”

“…Different classes of HIV‐1 entry inhibitors have been reviewed in several articles. The chemical structures and biological activity profiles of the inhibitors have been the subject of these reviews . In a review articles belonging to 2014, anti‐HIV‐1 agents have been discussed from the computer‐aided design point of view but, not all of the available HIV‐1 entry‐related targets were considered in that review article .…”

Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses

“…For all of the enveloped viruses with class I fusion protein, such as HIV, SARS-CoV, MERS-CoV, and EBOV, 6-HB formation is required to facilitate the fusion between virus and cell membrane. Small molecules that can block the formation of 6-HB are generally effective in inhibiting the infection of such viruses [91]. Since the first discovery of the potent HIV fusion inhibitory peptide SJ-2176 and clinical application of T20 for treatment of HIV infection [92,93], many viral fusion inhibitory peptides that can block the formation of 6-HB, such as HR2P and HR2P-M2 peptides against MERS-CoV and Tat-Ebo peptide against EBOV [18,30,55], have been reported.…”

Modifications in the branched arms of a class of dual inhibitors of HIV and EV71 replication expand their antiviral spectrum

“…Despite this, long-term side effects, latent viral infection within reservoirs and the development of drug resistance, weaken the efficacy of all clinically available drugs (Drug Resistance Data Base, 2018; Margolis, 2014;Rojas, 2014) highlighting the fact that new inhibitors and antiviral treatment strategies are constantly needed (Badia, 2017;Barreé-Sinoussi, 2013;Gulick, 2019a;Kumari, 2013;Tintori, 2014). In this sense, the initial steps in the HIV replicative cycle (entry and/or fusion with the host cells) are very attractive targets (Esté, 2011;Kang, 2013;Klase, 2012;Lu, 2016;Micewicz, 2013;Wensing, 2012).…”