Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target

Abstract

Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled-coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helicalhairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. They also suggest simple, quantitative assays for the identification and evaluation of analogous inhibitors of HIV-1 entry.

C-terminal Octylation Rescues an Inactive T20 Mutant

“…These peptides can be grouped in two distinctive classes: (i) C34 and its different analogs contain in their N termini the sequence WMEW, which is believed to fit into a deep cavity located at the opposite end of the N-terminal coiled coil (13,14), and (ii) T20 (formerly DP178) and its analogs, which are shifted toward the C terminus and therefore do not include these cavity-filling residues (15). The analogy between the structural organizations of gp41 and hemagglutinin, the fusion protein of influenza virus (16), and the inhibitory activity of gp41 Cpeptides lead to postulate a "pre-hairpin intermediate" in gp41-induced membrane fusion in which the N-terminal coiled coil is formed but the C-terminal helices are not packed (10,13).…”

Druggability analysis of membrane proteins by DoGSiteScorer

“…In Figure 2, three pockets of gp41 were identified by using the gp41 crustal structure PDB code 1AIK (David C. Chan et al, 1998) in DoGSiteScorer druggability analysis. Pocket_0 is located in the loop region that connecting NHR and CHR helixes.…”

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

“…In fact, we can see in the presented fusion model that the N-HR region exists in a non-coiled coil conformation in the native state, but forms a coiled coil trimer in the pre-hairpin intermediate and fusogenic hairpin conformations. During this process, the helical ectodomain of gp41 becomes exposed, revealing a prominent hydrophobic cavity on the surface of the gp41 N-terminal coiled coil that was identified as a potential antiviral target [89]. In fact, the approved inhibitor T-20 (enfurvitide) prevents gp41 from folding into a six-helical bundle by binding to the N-HR region in the pre-hairpin intermediate, as shown in Fig.…”