Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor

Abstract

One of the most critical requirements of the infection of the human immunodeficiency virus type 1 (HIV-1) is the interaction of its surface envelope glycoprotein gp120 with the cellular receptor CD4, which initiates virus entry to cells. Therefore, envelope glycoprotein gp120 has been validated as a potential target to develop HIV-1 entry inhibitors. Here we report the evaluation of a novel non-natural amino acid, termed 882376, reported earlier as a precursor of a CD4-mimetic miniprotein, as HIV-1 entry inhibitor. 882376 showed HIV-1 inhibitory activity against a large panel of primary isolates of different subtype. Moreover, genotyping of 882376 resistant HIV-1 virus revealed three amino acid substitutions in the gp120 including one in the CD4 binding site suggesting that this molecule may bind to gp120 and prevent its binding to CD4. Additional neutralization experiments indicate that 882376 is not active against mutant pseudoviruses carrying the amino acid substitutions S375H and S375Y located in the “Phe43 cavity” which is the major site of CD4 binding, suggesting that this compound may interfere with the interaction between gp120 and CD4. The unnatural amino acid, 882376, is expected to serve as a lead for further optimization to more potent HIV-1 entry inhibitors.

Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

“…Recently, we reported the structure-based design, synthesis, and evaluation of the small-molecule CD4-mimic DMJ-II-121 ( 3 ), a micromolar inhibitor of HIV-1 YU‑2 entry into human immune cells. , Like the initial congeners reported by Debnath et al (see 1 and 2 , Figure ), − 3 binds the Phe43 cavity of the viral envelope (Env) glycoprotein gp120, blocking CD4 binding and triggering a conformational change that ultimately results in viral inactivation.…”

Unusual Amino Acids in Medicinal Chemistry

“…The best (65a, 882376) had antiviral activity (IC 50 ) of 4.5 μM and low toxicity (CC 50 > 50 μM); the free amino acid 65b (882896) was inactive. 64 An arylalanine analogue of Trp is found as the central residue in calcitonin gene-related peptide (CGRP) antagonists under development by Bristol-Myers Squibb to treat migraine. Attempts were made to modify an initial lead suitable for intranasal dosing (66) (BMS-694153), to improve ADMET properties by varying the C-terminal components.…”

“…Aromatic amino acids, particularly substituted phenylalanine residues, have been very useful for SAR investigations during early drug discovery campaigns, as shown with 15 aniline-substituted 4′-amino-Phe amino acids that were found to act as HIV-1 entry inhibitors, possibly via blocking envelope glycoprotein gp120 binding to CD4. The best ( 65a , 882376) had antiviral activity (IC 50 ) of 4.5 μM and low toxicity (CC 50 > 50 μM); the free amino acid 65b (882896) was inactive . An arylalanine analogue of Trp is found as the central residue in calcitonin gene-related peptide (CGRP) antagonists under development by Bristol-Myers Squibb to treat migraine.…”

Antiviral Activity and Crystal Structures of HIV-1 gp120 Antagonists

“…On the contrary, Fostemsavir binds to an induced binding pocket under the β20-21 loop, distinct from the Ph43 cavity created upon CD4 binding. We reported the design, synthesis, antiviral activity, X-ray crystal structures, and preclinical assessments of many such NBDs [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Due to the critical role the structural information plays in designing inhibitors with improved binding and antiviral activity, we continue to strive to determine the crystal structures of NBDs to understand the binding interactions of this series of compounds in the Phe43 cavity.…”