Current insights into anti-HIV drug discovery and development: a review of recent patent literature (2014–2017)

ABSTRACT

Introduction: To deal with the rapid emergence of drug resistance challenges, together with the difficulty to eradicate the virus, off-target effects and significant cumulative drug toxicities, it is still imperative to develop next-generation anti-HIV agents with novel chemical classes or new mechanisms of action.

Areas covered: We primarily focused on current strategies to discover novel anti-HIV agents. Moreover, examples of anti-HIV lead compounds were mainly selected from recently patented publications (reported between 2014 and 2017). In particular, ‘privileged structure’-focused substituents decorating approach, scaffold hopping, natural-product diversification and prodrug are focused on. Furthermore, exploitation of new compounds with unexplored mechanisms of action and medicinal chemistry strategies to deplete the HIV reservoir were also described. Perspectives that could inspire future anti-HIV drug discovery are delineated.

Expert opinion: Even if a large number of patents have been disclosed recently, additional HIV inhibitors are still required, especially novel chemical skeletons displaying a unexploited mechanism of action. Current medicinal chemistry strategies are inadequate, and appropriate and new methodologies and technologies should be exploited to identify novel anti-HIV drug candidates in a time- and cost- effective manner.

KEYWORDS:

• HIV-1
• AIDS
• inhibitors
• drug design
• medicinal chemistry
• hit-to-lead optimization

Article highlights

• It is still imperative to develop next-generation anti-HIV agents with novel chemical classes via follow-on medicinal chemistry approaches.

• The ‘privileged structure’-focused substituents decorating, scaffold hopping, natural-product diversification and prodrug were considered to be the main approaches in anti-HIV drug discovery and development.

• The exploitation of new compounds with unexplored mechanisms of action is required very urgently.

• Medicinal chemistry strategies to deplete the HIV reservoir is still in explorative stage.

• The diversity-oriented synthesis (DOS) and target-focused synthesis should be used in combination to explore the chemical space of anti-HIV drug target systematically.

• The rapid assembly and screening of click chemistry-based combinatorial fragment libraries and DNA-encoded chemical libraries are promising strategies in seeking bioactive anti-HIV compounds.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have nothing to disclose.

Additional information

Funding

Financial support from the National Natural Science Foundation of China [NSFC No. 81573347, to P.Z.], the Fundamental Research Funds of Shandong University [No. 2017JC006, to P.Z.], Key Project of NSFC for International Cooperation [No. 81420108027, to X.L.], Young Scholars Program of Shandong University [YSPSDU No. 2016WLJH32, to P.Z.], and Key research and development plan of Shandong Province [No. 2017CXGC1401, to X.L.] is gratefully acknowledged.