Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity

Abstract

Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.

Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity

“…The x-ray structure of NBD-11021 bound to HIV-1 gp120 confirmed that this molecule binds to the Phe43 cavity 18 but in a slightly different orientation than we observed with NBD-556 and other partial antagonists such as NBD-09027 so that the piperidine “N” forms a H-bond with Asp368, a critical interaction that was missing in all our compounds so far. The wide breadth of anti-HIV-1 activity profile of NBD-11021 against a large panel of HIV-1 pseudoviruses representing diverse subtypes of clinical isolates and availability of its structural information in complex with gp120 motivated us to continue the design of more robust and active analogs of this molecule.…”

“…The basic synthesis routes to make this series of NBD-compounds have been previously reported 18 . First, we prepared imine 2 from racemic pipecolic acid and racemic tert -butanesulfinamide ( Scheme 1 ).…”

“…First, we prepared imine 2 from racemic pipecolic acid and racemic tert -butanesulfinamide ( Scheme 1 ). Then two protected thiazoles 4 and 9 were prepared from 5-(2-hydroxyethyl)-4-methylthiazole and thiazole 10 was prepared as reported 18 . 1,2-addition of thiazoles 10 and 4 to imine 2 yielded a separable mixture of isomeric products 11A/B and 12A/B and addition of thiazole 9 gave a single stereoisomer 13B .…”

“…We exploited the x-ray structural information of NBD-556 and other next generation NBD compounds bound to HIV-1 gp120 17 to design next generation CD4-mimics with the goal of achieving viral entry antagonist property. We recently reported the structure-based design of NBD-11021 which showed not only much potent broadly neutralizing activity but also this molecule was experimentally confirmed to be a viral entry antagonist, a much desired property of this class of molecules 18 .…”

"Unraveling Key Interactions That Leads the Stability of NBD-14010 Binding to Gp120 of Hiv-1: An Md Simulations and Free Energy Perspectives"

“…This study is expected to good step for new ways of designing more strong and effective HIV-1 entry inhibitors. As suggested from the x-ray structure of NBD-11021, it bounds to HIV-1 env gp120 and gives rise to a conclusion that this molecule binds to the Phe43 cavity 14 . The energetic contribution of each amino acid was verified at the binding site involved in stabilizing the complex, ( PDB: 5U6E) 15 …”