Novel compounds containing multiple guanide groups that bind the HIV coreceptor CXCR4.

Area of Science:

• Biochemistry
• Virology
• Medicinal Chemistry

Background:

• The G-protein-coupled receptor CXCR4 is essential for HIV-1 entry and involved in cell migration.
• Existing HIV entry inhibitors like maraviroc target CCR5; novel CXCR4 antagonists are needed.
• The peptide T140 is a potent CXCR4 antagonist, serving as a benchmark for new drug discovery.

Purpose of the Study:

• To discover nonpeptide small molecules that inhibit HIV-1 entry by blocking CXCR4.
• To synthesize and evaluate novel polyamine-derived guanidines, biguanides, and phenylguanides as CXCR4 ligands.

Main Methods:

• Synthesis of three series of compounds from 12 linear and branched polyamines.
• Testing compound ability to compete with T140 for binding to human CXCR4.
• Evaluating inhibition of X4 and R5 strains of HIV-1 infection in TZM-bl cells.

Main Results:

• Several synthesized compounds effectively bound CXCR4 with low nanomolar potency (IC50 ~200 nM) and low cytotoxicity.
• Spermine phenylguanide and spermidine phenylguanide inhibited X4-tropic HIV-1 infection at low micromolar concentrations.
• These compounds did not inhibit R5-tropic HIV-1 infection, indicating CXCR4 specificity.

Conclusions:

• Novel polyamine-derived phenylguanides are potent CXCR4 antagonists.
• These compounds demonstrate potential as specific inhibitors of X4-tropic HIV-1 entry.
• Further development of these nonpeptide ligands is warranted for HIV therapeutics.