Cyclotides as natural anti-HIV agents

Area of Science:

• Natural Product Chemistry
• Medicinal Chemistry
• Virology

Background:

• Cyclotides are macrocyclic plant peptides with a conserved cyclic cystine knot, conferring high stability.
• Over 100 cyclotides are known, exhibiting diverse biological activities, including anti-HIV effects.
• Möbius cyclotides are a subfamily hypothesized to be better drug candidates due to lower toxicity.

Purpose of the Study:

• To evaluate the anti-HIV and cytotoxic effects of three cyclotides, including two from the Möbius subfamily.
• To explore structure-activity relationships (SARs) for anti-HIV activity among cyclotides.
• To compile existing cyclotide anti-HIV data into a comprehensive resource.

Main Methods:

• Assessed anti-HIV activity and cytotoxicity of selected cyclotides.
• Modeled structures of 21 cyclotides lacking solved structures.
• Analyzed correlations between structural features (hydrophobicity, charged residues) and anti-HIV activity.

Main Results:

• Möbius cyclotides demonstrated comparable HIV inhibition to bracelet cyclotides but with significantly lower cytotoxicity.
• Structural modeling revealed correlations between loop region hydrophobicity and HIV inhibition within cyclotide subfamilies.
• Charged residues in loop regions were found to influence cyclotide activity, likely by modulating membrane binding.

Conclusions:

• Möbius cyclotides represent promising natural anti-HIV agents with a favorable safety profile.
• Cyclotide structure-activity relationships are influenced by loop region hydrophobicity and charge.
• This study provides valuable SAR data and consolidates information for future therapeutic development of cyclotides against HIV.