HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2′ Ligands To Optimize Hydrogen Bonding in the Substrate Envelope

Abstract

A structure-guided design strategy was used to improve the resistance profile of HIV-1 protease inhibitors by optimizing hydrogen bonding and van der Waals interactions with the protease while staying within the substrate envelope. Stereoisomers of 4-(1-hydroxyethyl)­benzene and 4-(1,2-dihydroxyethyl)­benzene moieties were explored as P2′ ligands providing pairs of diastereoisomers epimeric at P2′, which exhibited distinct potency profiles depending on the configuration of the hydroxyl group and size of the P1′ group. While compounds with the 4-(1-hydroxyethyl)­benzene P2′ moiety maintained excellent antiviral potency against a panel of multidrug-resistant HIV-1 strains, analogues with the polar 4-(1,2-dihydroxyethyl)­benzene moiety were less potent, and only the (R)-epimer incorporating a larger 2-ethylbutyl P1′ group showed improved potency. Crystal structures of protease–inhibitor complexes revealed strong hydrogen bonding interactions of both (R)- and (S)-stereoisomers of the hydroxyethyl group with Asp30′. Notably, the (R)-dihydroxyethyl group was involved in a unique pattern of direct hydrogen bonding interactions with the backbone amides of Asp29′ and Asp30′. The SAR data and analysis of crystal structures provide insights for optimizing these promising HIV-1 protease inhibitors.

A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities

“…Many previous studies have demonstrated that targeting the primed site can be an effective strategy for developing potent or selective inhibitors of proteases of viruses such as human immunodeficiency virus and hepatitis C virus [ [25] , [26] , [27] ]. Recently, several groups have reported α-keto phenylamide and epoxyketone based proteasome inhibitors targeting the primed site to increase potency or overcome resistance [ 21 , 45 ].…”

“…1 A) [ 24 ]. Previous studies have utilized the primed site to improve the specificity and potency of protease inhibitors [ [25] , [26] , [27] ]. In this study, we incorporated different substitutions into α-keto phenylamide's head group to examine their effects on the proteasome inhibitory potency.…”

Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study

“…The 4-trifluoromethyl group in the P2'-ligand may cause favorable halogen interactions and van der Waals interactions with the P2'-pocket [30,31], in spite of its weak electron-withdrawing inductive effect that impaired the binding affinity slightly [15]. Although the amino of 4-aminobenzene sulfonamide could participate in direct or water-mediated hydrogen bonds with Asp30', these interactions were weaker than those between 4-methoxybenzene sulfonamide and the cavity of S2 Appendix-subsite [10]. On the contrary, the strong electron-withdrawing property of nitro in the P2'-ligand, including both electron-withdrawing inductive effect and conjugation, was likely to weaken not only the hydrogen bonds between the nitro oxygen and Asp30', but also the water-mediated interactions between the sulfonyl oxygen and Ile50' [19,15].…”

“…HIV-1 PIs serve as a critical therapeutic approach for the treatment of HIV-1 infection due to their ability to block the production of viral proteins for mature virions [4][5][6]. So the design of potent PIs continues to be essential for long-term control of HIV-1 infection and AIDS [7][8][9][10].…”

Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere

“…EC 50 was determined based on a dose-response curve generated using GraphPad Prism (version 7.0).Protein Crystallization. The condition reliably producing cocrystals of NL4-3 WT protease bound to PIs was discovered and optimized as previously described 40,43. Briefly, all cocrystals were grown at room temperature by hanging drop vapor diffusion method in a 24-well VDX hanging-drop trays (Hampton Research) with a protease concentration of 1.4-1.7 mg/mL with 3-fold molar excess of inhibitors and mixed with the precipitant solution at a 1:2 ratio.…”