HIV-1 Maturation Inhibitors and Capsid Inhibitors

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

For over 20 years, we have been making steady progress in developing MIs as a new class of antiretroviral drug. We and others in the field have used our lead compounds as molecular probes to understand basic aspects of HIV-1 assembly and maturation. MIs act by blocking the processing of the CA-SP1 Gag cleavage intermediate to CA, thereby interfering with particle maturation and infectivity. Our studies have provided key insights into both the mechanism of action of this emerging class of inhibitor and the roles of the CA-SP1 region of Gag, which folds into a six-helix bundle, in assembly and maturation. The overarching concept is that the stability of the six-helix bundle is balanced in a manner that promotes assembly yet permits PR-mediated processing. MIs disturb this critical balance by binding within, and stabilizing, the six-helix bundle. Because the CA-SP1 cleavage site is buried within the bundle, its stabilization by MIs prevents PR access to the cleavage site. Much of our effort has been focused on deciphering the mechanism of action of these compounds and understanding viral resistance pathways. We have combined compound screening, drug resistance analyses, and structural biology approaches pursued in collaboration with other groups. The first-in-class MI bevirimat (BVM), whose mechanism of action we first reported in 2003, was tested in phase II clinical trials by our collaborators at Panacos Pharmaceuticals in the mid 2000s; although BVM was shown to be safe and effective as an antiviral agent in humans, amino acid polymorphisms in the CA-SP1 region limited compound efficacy in some clinical trial participants. Our current work, and that of others, is focused on developing "second-generation" MIs that overcome this issue and are highly potent against a wide range of HIV 1 subtypes (aim a); our work is being performed in collaboration with Hetero Drugs and DFH Pharma. We (the NCI) share intellectual property on the most potent DFH Pharma compounds. We will perform studies aimed at deciphering the molecular and structural basis for the improved activity of second-generation MIs. Because most of the work on MI resistance has been done in the context of lab-adapted, subtype B isolates (primarily NL4-3), and because it is clear that sequence polymorphisms outside the CA-SP1 bundle affect MI susceptibility, we are also engaged in studies that seek to better understand the basis for differential MI susceptibility of different subtypes of HIV-1, and to elucidate the basis for MI resistance. The HIV-1 capsid has become of great interest as a target for antiretrovirals. Gilead Sciences recently reported the development of the subnanomolar capsid inhibitor GS-6207 (Lenacapavir; LEN). LEN has shown efficacy in clinical trials as a long-acting antiretroviral with twice-yearly dosing and in 2022 was approved by the FDA for salvage therapy. Furthermore, two recent phase 3 clinical trials evaluating LEN for pre-exposure prophylaxis (PrEP) produced promising results. LEN most potently inhibits early stages of the HIV-1 replication cycle, disrupting reverse transcription, nuclear entry, and integration but also inhibits assembly and maturation. Although LEN exhibits remarkably potent antiviral activity, in vitro studies and clinical trial data indicate that resistance to LEN can emerge. In Aim c, we propose studies designed to elucidate capsid inhibitor resistance pathways and describe work with collaborators to develop capsid inhibitors that are active against LEN-resistant mutants. This project contains several specific aims: a) Develop potent and broadly active HIV-1 MIs for clinical testing, b). Understand the molecular, biochemical, and structural basis for MI activity and resistance pathways, and c). Test novel capsid inhibitors and elucidate capsid inhibitor resistance pathways. U.S. Patent #11236122: "Triterpene Amine Derivatives"; issued January 2, 2022; Theodore J. Nitz, Carl T. Wild, David E. Martin, and Eric O. Freed.