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.

Fig. 1. A model of HIV-1 entry into the target cell and the crystal structures of HIV-1 gp120 and gp41 core

A) A model of HIV-1 fusion and entry. (i) the crystal structures of gp120 (adapted from [135] with permission); (ii) gp120 core in complex with two membrane-distal domains of CD4 and the Fab fraction of an antibody X5 (adapted from [45] with permission); (iii) the HIV-1 gp120 core in complex with CD4, and the gp41-interactive residues identified by mutation analysis (adapted from [46] with permission). B) Crystal structure of gp41 core (adapted from ref [13] with permission). (i) side-view of the 6-HB core formed by N36 and C34 peptides; (ii) top-view of the 6-HB core; (iii) three conserved hydrophobic residues (W628, W631, and I635) in the gp41 CHR region binding to the hydrophobic pocket; and (iv) the deep pocket of gp41 NHR and its interaction with the WWI motif in CHR. C) Model of HIV-1 gp41-mediated membrane fusion. HIV-1 entry into the target cell is initiated by gp120 binding to CD4 and then to CCR5 or CXCR4, followed by conformational change of gp41. The fusion peptide (FP) at the N-terminus of gp41 inserts into the target cell membrane and the NHR and CHR regions in gp41 interact with each other to form 6-HB, which brings the HIV-1 envelope and the target cell membrane into close proximity for fusion.

Fig. 2. HIV entry inhibitors specifically targeting gp120

A) Chemical structures of BMS-378806 and its derivatives. B) Chemical structure of NBD-556. C) Chemical structures of JRC-II-191. D) Chemical structures of compound 6 (NBD-09027). E) GLIDE-based docking of compound 6 in the Phe43 cavity. The 4-chlorophenyl moiety of compound 6 is located deep inside the cavity, and the protonated “N” of piperidine ring is within salt-bridge (H-bond interaction) distance from Asp368 (adapted from [75] with permission).

Fig. 3. Chemical structures of HIV entry inhibitors targeting gp41

IC₅₀ values with “*” were calculated based on the data from the experiments for inhibiting HIV-1 Env-mediated cell-cell fusion, while those without “*” were calculated based on the data from the experiments for inhibiting HIV-1 infection.

Fig. 3. Chemical structures of HIV entry inhibitors targeting gp41

IC₅₀ values with “*” were calculated based on the data from the experiments for inhibiting HIV-1 Env-mediated cell-cell fusion, while those without “*” were calculated based on the data from the experiments for inhibiting HIV-1 infection.

Fig. 3. Chemical structures of HIV entry inhibitors targeting gp41

IC₅₀ values with “*” were calculated based on the data from the experiments for inhibiting HIV-1 Env-mediated cell-cell fusion, while those without “*” were calculated based on the data from the experiments for inhibiting HIV-1 infection.