Recent Advances in HIV-1 Gag Inhibitor Design and Development.

Alexej Dick,Simon Cocklin

doi:10.3390/molecules25071687

Abstract

Acquired Immune Deficiency Syndrome (AIDS) treatment with combination antiretroviral therapy (cART) has improved the life quality of many patients since its implementation. However, resistance mutations and the accumulation of severe side effects associated with cART remain enormous challenges that need to be addressed with the continual design and redesign of anti-HIV drugs. In this review, we focus on the importance of the HIV-1 Gag polyprotein as the master coordinator of HIV-1 assembly and maturation and as an emerging drug target. Due to its multiple roles in the HIV-1 life cycle, the individual Gag domains are attractive but also challenging targets for inhibitor design. However, recent encouraging developments in targeting the Gag domains such as the capsid protein with highly potent and potentially long-acting inhibitors, as well as the exploration and successful targeting of challenging HIV-1 proteins such as the matrix protein, have demonstrated the therapeutic viability of this important protein. Such Gag-directed inhibitors have great potential for combating the AIDS pandemic and to be useful tools to dissect HIV-1 biology.

Highlights

Introduction and Current Status of AntiretroviralTherapiesAIDS (Acquired Immune Deficiency Syndrome) is a global epidemic caused by HIV infection [1]
We focus on the importance of the HIV-1 Gag polyprotein as the master coordinator of HIV-1 assembly and maturation and as an emerging drug target
We describe topologically the importance of targeting the HIV-1 Gag polyprotein and its component domains for the development of novel antivirals

Summary

Introduction and Current Status of Antiretroviral Therapies

AIDS (Acquired Immune Deficiency Syndrome) is a global epidemic caused by HIV (human immune-deficient virus) infection [1]. Long-term cART therapy leads to side effects and age-related comorbidities such as diabetes, cardiovascular, renal, and bone diseases and can result in a reduced life expectancy of HIV-1 infected patients [7,8]. This highlights the continued need for new antiretroviral drugs with low cytotoxicity, long-acting formulations, and new targets in the HIV-1 replication cycle. One such emerging therapeutic target is the HIV-1 Gag protein, which is the master regulator of co-factor packaging, assembly, and release of the immature virion. In addition to current Gag-targeted inhibitors, we highlight some of the new developments for each Gag domain and speculate, based on these recent findings, on possible future antiviral designs

The Gag Polyprotein and Its Role in the HIV-1 Replication Cycle

HIV-1 Protease and Maturation Inhibitors

Zinc-Ejectors

Small Molecules as Non-Zinc Ejectors

Findings

Conclusions