Function-Oriented Development of CXCR4 Antagonists as Selective Human Immunodeficiency Virus (HIV)-1 Entry Inhibitors

Abstract

Motivated by the pivotal role of CXCR4 as an HIV entry coreceptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound 24 complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound 24 showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4+/CD34+ stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function.

Proteins, peptides, polysaccharides, and nucleotides with inhibitory activity on human immunodeficiency virus and its enzymes

“…Plerixafor and its derivatives which are CXCR4 antagonists have also demonstrated anti-HIV activity. CXCR4 act as HIV entry co-receptors can function as a HIV entry inhibitors (Wu et al 2015). Preclinical studies have shown that the anti-glucocorticoid drug mifepristone interfered with HIV-1 vpr (a regulatory protein of cellular processes linked to the HIV life cycle) function and effectively inhibited HIV replication.…”

Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology

“…Dual modifications at both the 6‐ and 7‐position on the quinazoline ring with methoxy groups in compounds 110 , 113, and 116 did not further increase their binding affinities to CXCR4, suggesting that hydrophobic interactions could be involved for the binding (Fig. ) . Despite strong CXCR4 binding by quinazoline compounds 108 , 109 , 111 , and 112 with IC 50 values around 10 nM, only compound 86 showed a significant eightfold increase (EC 50 = 8.6 nM) in the blockade of HIV‐1 infection compared to compound 95 .…”

“…Besides apoptosis, autophagy in T cells can also be induced by gp120/CXCR4 interaction . The development of CXCR4 antagonists to disrupt gp120/CXCR4 interaction will be invaluable toward combating HIV‐1 infections . Although ACKR3 and CXCR4 are similar in property for ligand binding, interaction of ACKR3 with HIV‐1 envelope proteins, such as gp120, still needs to be identified.…”

“…In a separate study, the potential of these quinazoline‐based CXCR4 antagonists in the blockade of HIV‐1 entry was evaluated by luciferase activity assays using TZM‐bl cells . Compounds 92 – 96 with terminal ring‐size expansion from three‐ to seven‐membered ring showed increased binding affinities toward the CXCR4 receptor and relatively good correlation with their anti‐HIV‐1 activities …”

“…Surprisingly, by swapping the orientation of the two projected peripheries, the CXCR4 binding affinity of compound 117 was restored to 18.1 nM (Fig. ) …”