Small Molecule HIV-1 Attachment Inhibitors: Discovery, Mode of Action and Structural Basis of Inhibition

Abstract

Viral entry into host cells is a critical step in the viral life cycle. HIV-1 entry is mediated by the sole surface envelope glycoprotein Env and is initiated by the interaction between Env and the host receptor CD4. This interaction, referred to as the attachment step, has long been considered an attractive target for inhibitor discovery and development. Fostemsavir, recently approved by the FDA, represents the first-in-class drug in the attachment inhibitor class. This review focuses on the discovery of temsavir (the active compound of fostemsavir) and analogs, mechanistic studies that elucidated the mode of action, and structural studies that revealed atomic details of the interaction between HIV-1 Env and attachment inhibitors. Challenges associated with emerging resistance mutations to the attachment inhibitors and the development of next-generation attachment inhibitors are also highlighted.

Keywords: HIV-1 entry; antiviral activity; attachment inhibitors; crystal structures; fostemsavir; temsavir.

Figure 1

The HIV-1 entry process and FDA-approved drugs inhibiting this process. The HIV-1 entry is a complex process involving many steps. Four FDA-approved drugs targeting different steps of the HIV-1 entry are shown. These include fostemsavir that blocks CD4 binding (attachment inhibitor class), ibalizumab targeting the domain II of CD4 receptor (post-attachment inhibitor class), maraviroc binding to CCR5 coreceptor (CCR5 antagonist class), and enfuvirtide binding to gp41 (fusion inhibitor class). Figure was prepared in BioRender.

Figure 2

Chemical structures of temsavir and analogues. Two-dimensional chemical structures are shown for each compound. Three-dimensional structures of BMS-378806, BMS-626529 (temsavir), BMS-818251, and compound 484 in complex with HIV-1 envelope protein have been determined (see Figure 3). Compounds 87 and 88 were based on the numbering from reference [32]. Computational models of compounds 87 and 88 in complex with HIV-1 Env are also available in reference [32].

Figure 3

Binding sites of temsavir and related compounds on HIV-1 Env. (a) One protomer of the Env trimer is shown as ribbon with transparent surface, while the other two protomers are shown as solid surfaces in green and blue. CD4 binding site is shown as yellow surface patch. A temsavir analog BMS-818251 is represented as orange spheres. (b) Two partially overlapping but distinct inhibitor binding sites are present in the vicinity of CD4 binding site. Inhibitors with available complex structures are shown superimposed. Inhibitors binding to site 1 are colored in orange/brown shades and include BMS-626529 (temsavir; PDB: 5U7O), BMS-378806 (PDB:6MTJ), BMS-818251 (PDB:6MU7), BMS-814508 (PDB:6MU6), BMS-386150 (PDB:6MU8) and compound 484 (PDB:6MTN). Inhibitors binding to site 2 are colored in blue/purple shades and include NBD-556 (PDB:3TGS), NBD-10007 (PDB: 4DKV), and DMJ-II-121 (PDB: 4I53). Detailed interactions between HIV-1 Env and BMS-378806, BMS-626529 (temsavir), and BMS-818251 are shown in panels (c–e), respectively. b20-b21 hairpin (residues 423–436) is shown as green ribbon. The C-terminus of a1 helix (residues 107–117) is shown as cyan ribbon, and part of CD4-binding loop (residues 369–385) is shown as magenta ribbon. The b20-b21 hairpin is removed in the lower panels of (c–e) for clarity. HIV-1 Env residues that interact directly with inhibitors are shown as sticks with residue type and number labeled. Figure 3e was originally published in Nat Commun 10, 47 (2019) [52].