Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends

Abstract

The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus.

Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 4‐[4‐Arylpyridin‐1(4H)‐yl]benzoic Acid Derivatives as Anti‐HIV‐1 Agents

“…A drug protocol called highly‐active antiretroviral therapy (HAART) applies a combination of anti‐retroviral drugs, generally including two different nucleoside reverse transcriptase inhibitors and an non‐nucleoside reverse transcriptase inhibitor or a protease inhibitor . Because of the serious adverse effects, drug resistance and increased number of patients of HIV‐1 infection who fail to respond to HAART, development of novel anti‐HIV‐1 drugs is necessitated …”

“…[1] Because of the serious adverse effects, drug resistance and increased number of patients of HIV-1 infection who fail to respond to HAART, development of novel anti-HIV-1 drugs is necessitated. [2] [3] Viral entry, the first step of HIV-1 infection, is a promising step for anti HIV-1 drug design. [4][5] It consists of the attachment of the viral and target cell membranes, a procedure mediated by a series of molecular events involving viral envelope proteins, gp120 and gp41.…”

Novel 4‐arylaminoquinoline‐3‐carbonitriles as Inhibitors of HIV‐1 Reverse Transcriptase

“…Many drugs have been developed to try to inhibit the replication of HIV. Reverse transcriptase (RT) is considered a key enzyme in the replication cycle of retroviruses and has been widely used as a tool to search compounds having antiviral potential .…”

Modifications in the branched arms of a class of dual inhibitors of HIV and EV71 replication expand their antiviral spectrum

“…Human immunodeficiency virus (HIV) is the etiologic agent of the Acquired Immunodeficiency Syndrome (AIDS), a devastating infectious disease that continues to be a major global public health problem (UNAIDS DATA, 2018;WHO, 2018). The use of antiretroviral therapy (ART) has improved life expectancy and transformed HIV-1 infection into a manageable chronic disease (Arts, 2012;Broder, 2010;Mehellou, 2010;Volberding, 2010;Zhan, 2016). Despite this, long-term side effects, latent viral infection within reservoirs and the development of drug resistance, weaken the efficacy of all clinically available drugs (Drug Resistance Data Base, 2018; Margolis, 2014;Rojas, 2014) highlighting the fact that new inhibitors and antiviral treatment strategies are constantly needed (Badia, 2017;Barreé-Sinoussi, 2013;Gulick, 2019a;Kumari, 2013;Tintori, 2014).…”