[Development of selective antagonists against an HIV second receptor]

Area of Science:

• Medicinal Chemistry
• Virology
• Immunology

Background:

• Human Immunodeficiency Virus type 1 (HIV-1) entry into T-cells relies on co-receptors, notably CXCR4 for T-cell line-tropic strains (X4-HIV-1).
• Horseshoe crab defense peptides, tachyplesins and polyphemusins, serve as a basis for developing novel antiviral agents.
• Structure-activity relationship (SAR) studies are crucial for optimizing peptide-based therapeutics.

Purpose of the Study:

• To discover and synthesize highly selective CXCR4 antagonists for inhibiting X4-HIV-1 infection.
• To evaluate the anti-HIV activity and CXCR4 antagonism of novel peptide analogs.
• To develop efficient synthetic methodologies for peptide-based drug discovery.

Main Methods:

• Structure-activity relationship (SAR) studies on horseshoe crab defense peptides.
• Synthesis and evaluation of novel peptide analogs (T140, TC14012) and bifunctional agents.
• Development of facile and side-reaction-free disulfide bond formation and stereocontrolled synthesis of peptide isosteres.

Main Results:

• Discovery of T22, T140, and TC14012 as potent and selective CXCR4 antagonists.
• T140 and TC14012 exhibit the highest reported anti-HIV activity and CXCR4 antagonism.
• Successful synthesis of bifunctional anti-HIV agents by conjugating T140 analogs with AZT.
• Establishment of efficient synthetic methodologies for peptide and peptide mimetic synthesis.

Conclusions:

• Novel peptide antagonists targeting the CXCR4 co-receptor offer a promising strategy against X4-HIV-1 infection.
• The developed synthetic methods enhance the efficiency of SAR studies and peptide-based drug development.
• These CXCR4 antagonists hold potential as therapeutic agents and drug delivery carriers for HIV treatment.