Antiviral Breadth and Combination Potential of Peptide Triazole HIV-1 Entry Inhibitors

Abstract

The first stage of human immunodeficiency virus type 1 (HIV-1) infection involves the fusion of viral and host cellular membranes mediated by viral envelope glycoprotein gp120. Inhibitors that specifically target gp120 are gaining increased attention as therapeutics or preventatives to prevent the spread of HIV-1. One promising new group of inhibitors is the peptide triazoles, which bind to gp120 and simultaneously block its interaction with both CD4 and the coreceptor. In this study, we assessed the most potent peptide triazole, HNG-156, for inhibitory breadth, cytotoxicity, and efficacy, both alone and in combination with other antiviral compounds, against HIV-1. HNG-156 inhibited a panel of 16 subtype B and C isolates of HIV-1 in a single-round infection assay. Inhibition of cell infection by replication-competent clinical isolates of HIV-1 was also observed with HNG-156. We found that HNG-156 had a greater than predicted effect when combined with several other entry inhibitors or the reverse transcriptase inhibitor tenofovir. Overall, we find that HNG-156 is noncytotoxic, has a broad inhibition profile, and provides a positive combination with several inhibitors of the HIV-1 life cycle. These results support the pursuit of efficacy and toxicity analyses in more advanced cell and animal models to develop peptide triazole family inhibitors of HIV-1 into antagonists of HIV-1 infection.

Peptide Triazole Inactivators of HIV-1 Utilize a Conserved Two-Cavity Binding Site at the Junction of the Inner and Outer Domains of Env gp120

“…10 Strikingly, in addition to being potent cell infection inhibitors, this class of compounds induces shedding of gp120, thus inactivating the virus before cell encounter. 11 In addition, peptide triazole thiols (PTTs), PTs containing a free sulfhydryl group (SH) on Cys at the C-terminus, cause envelope disruption and p24 capsid protein release from the virus lumen.…”

Disulfide Sensitivity in the Env Protein Underlies Lytic Inactivation of HIV-1 by Peptide Triazole Thiols

“…We also evaluated the effect of cyanovirin-N, a lectin that binds high-mannose glycans in the gp120 outer domain, which has been observed before to not compete with peptide triazole binding. 20 In contrast to 2G12, cyanovirin-N did not inhibit p24 release induced by the PTTs 1 , 2 , or 8 (Figure 5B). Based on the docking model of Figure 6, another possible site of disulfide interaction is located in the V1/V2 loop encompassing the disulfide C119–C205.…”

“…The broadly neutralizing gp120 antibody 2G12 has previously been shown to bind to the mannose-rich epitope at the base of the gp120 V3 loop 19 but to not affect PT binding 20 (Figure 5D). Inhibition assays with 2G12 were performed with 1 (positive control), 2 (the longest of the truncated virolytic peptides), and 8 (the shortest peptide truncate that still causes observable p24 release).…”

Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators

“…The structures, gp120 binding potencies, and antiviral activities of the peptide triazoles HNG-156, KR13, and UM15 utilized in this study have been described previously. 5,19,26 All of these compounds (added to the viral suspensions 30 min before infection) were found to exert a dose-dependent inhibitory effect on the HIV infection of B-THP-1/DC-SIGN cells. At (Fig.…”

“…Peptide triazoles are also not toxic to cells at the studied concentrations. 19,26 There is an urgent need to develop new effective and affordable strategies against HIV, taking into account the chronic character of this disease (in case of permanent treatment) that necessitates the use of drugs with the lowest side effects possible. 30 To the best of our knowledge, this is the first study to apply dextran/oligodextran as a base for the development of biocompatible DC-SIGN and MR (CD206) ligands in the setting of infections including HIV and tuberculosis.…”