Opening the HIV Envelope: Potential of CD4 mimics as multifunctional HIV entry inhibitors

PURPOSE OF REVIEW: Close to two million individuals globally become infected with human immunodeficiency virus (HIV-1) each year and just over two thirds will have access to life-prolonging antivirals. However, the rapid development of drug resistance creates challenges, such that generation of more effective therapies is not only warranted but a necessary endeavour. This review discusses a group of HIV-1 entry inhibitors known as CD4 mimics which exploit the highly conserved relationship between the HIV-1 envelope glycoprotein (Env) and the receptor, CD4. RECENT FINDINGS: We review the structure/function guided evolution of these inhibitors, vital mechanistic insights that underpin broad and potent functional antagonism, recent evidence of utility demonstrated in animal and physiologically relevant in vitro models, and current progress towards effective new-generation inhibitors. SUMMARY: This review highlights the promising potential of CD4 mimetics as multifunctional therapeutics.