NEW LONG ACTING HIV DRUG CLASS ON THE HORIZON – CAPSID INHIBITORS

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Capsid assembly is the step in the HIV lifecycle where the virus develops a cone-shaped core (capsid) particle, which contains or encloses the viral genetic blueprint (genome), inside a maturing infectious virion. It consists of a protein envelop membrane which protects the viral antigen core genetic proteins (called “p24”). Once released inside the host human cell, the core capsid particle disassembles to allow the core viral proteins to integrate into the host cell nucleus, and then go on to bud and mature from that cell, and so enter and infect further cells. Capsid inhibition (at the assembly and disassembly steps) is a previously unexplored target for HIV antiviral therapy – and so is a novel new drug class (type) for HIV treatment in early development. The pre-clinical results of the first capsid inhibitor GS-CA1 (being developed by Gilead) were presented at the CROI conference, showing the potential role of this new class of therapy as a low dose, long-acting injectable HIV treatment.

GC-CA1 creates a defective capsid core particle within the HIV virion which makes it  non-replicating and non-infectious. The preclinical study found that GS-CA1, is a highly potent inhibitor of HIV-1 replication (“more potent” than existing antiretrovirals) as studied in human (laboratory harvested) blood cells, and displays similar potency against multiple HIV sub-types (clades). The study also found that the identified CAIs bind to a broadly conserved site (affinity with the binding site), and maintains full activity in vitro against HIV mutations resistant to current licensed antiretrovirals (ARVs). Preclinical studies revealed a dual mode of action targeting both the late-stage virion maturation (in blood) and post-entry (into the host cell) capsid functions. Though designed to target capsid assembly, researchers found that the inhibitor acts at multiple steps in the viral replication cycle, interfering with capsid assembly necessary for late-stage virion (viral particle) maturation, as well as functions that occur after entry into a host cell such as capsid disassembly and moving viral genetic material into the cell nucleus. GS-CA1 showed high in vitro (laboratory) metabolic stability and displayed an extended-release preclinical drug level profile following a single subcutaneous administration (in rats) that maintained target plasma concentrations for over 10 weeks.

Gilead plans to commence Phase 1 human clinical trials in 2018, using low dose injections administered no more than once a month. So far GS-CA1 has shown no toxicity in target cells, but further toxicology studies will be conducted according to the Gilead press release.

GS-CA1 Mode of Action Summary

 

Reference: Tse WC et al. Discovery of novel potent HIV capsid inhibitors with long-acting potential. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 38, 2017.

View the abstract on the conference website.

View a webcast of this presentation on the conference website.

Source:

Adapted from www.natap.org (Ref: Gilead Press Release): http://www.gilead.com/news/press-releases/2017/2/gilead-announces-findings-from-new-preclinical-study-evaluating-novel-class-of-hiv-capsid-inhibitors

Adapted from article by Liz Highleyman, produced in collaboration with hivandhepatitis.com 
Published:03 March 2017 http://www.aidsmap.com/New-HIV-capsid-inhibitors-show-high-potency-and-prolonged-activity-in-early-studies/page/3121280/

Further Technical Reading: Large-Scale Functional Purification of Recombinant HIV-1 Capsid. 
Magdeleine Hung, Anita Niedziela-Majka, Debi Jin, Melanie Wong, Stephanie Leavitt, Katherine M. 
Brendza, Xiaohong Liu, Roman Sakowicz. Research Article | published 05 Mar 2013 P. http://dx.doi.org/10.1371/journal.pone.0058035