This study states that The acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV), has been a global public health challenge for several decades. The majority of HIV infection is caused by the human immunodeficiency virus type 1 (HIV-1), which enters and infects a host cell via the cell surface proteins of CD4 as the primary receptor, and chemokine receptors CXCR4 or CCR5 as the coreceptor–then undergoing replication using the cell’s intracellular machinery. Whereas many drugs targeting CCR5-mediated entry of HIV-1 replication via reverse transcriptase or proteases have long been used clinically, agents targeting CXCR4 are yet to be advanced to clinical application. Here in this review, we highlight some of the strategies for and progress made in the discovery of novel small molecules, peptides, and larger molecules that target CXCR4, and their future prospects for translation into the clinic as a new class of anti-HIV therapeutics.

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