Enhancing Protein Backbone Binding—A Fruitful Concept for Combating Drug‐Resistant HIV

Abstract

The evolution of drug resistance is one of the most fundamental problems in medicine. In HIV/AIDS, the rapid emergence of drug-resistant HIV-1 variants is a major obstacle to current treatments. HIV-1 protease inhibitors are essential components of present antiretroviral therapies. However, with these protease inhibitors, resistance occurs through viral mutations that alter inhibitor binding, resulting in a loss of efficacy. This loss of potency has raised serious questions with regard to effective long-term antiretroviral therapy for HIV/AIDS. In this context, our research has focused on designing inhibitors that form extensive hydrogen-bonding interactions with the enzyme's backbone in the active site. In doing so, we limit the protease's ability to acquire drug resistance as the geometry of the catalytic site must be conserved to maintain functionality. In this Review, we examine the underlying principles of enzyme structure that support our backbone-binding concept as an effective means to combat drug resistance and highlight their application in our recent work on antiviral HIV-1 protease inhibitors.

Design of Highly Potent, Dual‐Acting and Central‐Nervous‐System‐Penetrating HIV‐1 Protease Inhibitors with Excellent Potency against Multidrug‐Resistant HIV‐1 Variants

“…The latest approved PI, darunavir (DRV, 1 , Figure 1), is the only PI drug recommended for first-line therapy. [10–12] It exhibits a high genetic barrier and it is the most widely prescribed PI for treatment-experienced and treatment-naïve patients with HIV-1 infection and AIDS. [13] This is possibly due to darunavir’s dual mechanism of action as 1) an inhibitor of catalytic HIV-1 protease, and 2) an inhibitor of the dimerization of protease monomers.…”

“…[10, 21–23] Herein, we report a novel HIV-1 PI containing a 6-5-5-ring-fused crown-like tetrahydropyranofuran as the P2-ligand, an aminobenzothiazole as the P2′-ligand, and a two-fluorine containing phenylalanine side chain as the P1-ligand. The resulting PI exhibited unprecedented antiviral activity against a wide range of highly multidrug-resistant HIV-1 variants, and displayed high genetic barrier against the emergence of resistant variants.…”

A Conserved Hydrogen-Bonding Network of P2 bis -Tetrahydrofuran-Containing HIV-1 Protease Inhibitors (PIs) with a Protease Active-Site Amino Acid Backbone Aids in Their Activity against PI-Resistant HIV

“…Darunavir (DRV) (Fig. 1), the latest FDA-approved protease inhibitor (PI), which contains bis-tetrahydrofuranyl urethane (bis-THF) as the P2 moiety, has been shown to have a high genetic barrier (5,6), a feature of a drug or regimen that delays or prevents the occurrence of genetic evolution of HIV-1 to acquire drug resistance-associated mutations, allowing the virus to overcome the antiretroviral activity of the very drug or regimen and to become capable of propagating despite treatment with the very drug or regimen. However, HIV-1 also ultimately develops high levels of resistance to DRV both in vitro and in vivo (7,8).…”

An enantioselective enzymatic desymmetrization route to hexahydro-4H-furopyranol, a high-affinity ligand for HIV-1 protease inhibitors

“…16 Structurally, darunavir was designed to make extensive interactions in the active site of HIV-1 protease, particularly with the backbone atoms from S2 and S2′ subsites. 9,17 …”

“…10,17 Interestingly, the ring-fusion, stereochemistry, and position of urethane are critical to inhibitor potency. Inhibitor 3 , with a (3 R, 3a S, 7a R )-hexahydro-4 H -furo[2,3- b ]pyran-3-ol, is significantly less potent than inhibitors 1 and 2 .…”