Synthetic Natural Product Inspired Cyclic Peptides

Area of Science:

• Biochemistry
• Synthetic Biology
• Medicinal Chemistry

Background:

• Natural products are vital sources of bioactive molecules, but their discovery is hindered by complex biosynthetic pathways and purification challenges.
• Novel bioactive molecule discovery remains a critical need, particularly for combating antibiotic resistance.

Purpose of the Study:

• To develop and validate a novel method, SNaPP (Synthetic Natural Product Inspired Cyclic Peptides), for expedited identification of NP-inspired bioactive peptides.
• To leverage bioinformatics and chemical synthesis to create a library of cyclic peptides with potential therapeutic applications.

Main Methods:

• SNaPP integrates bioinformatics predictions of nonribosomal peptide synthetases with chemical synthesis of predicted natural products (pNPs).
• A penicillin binding protein-like cyclase was employed for the synthesis of head-to-tail cyclic peptide pNPs.
• Solid-phase peptide synthesis and solution-phase cyclization were used to generate a library of 51 diverse pNPs from 131 identified novel candidates.

Main Results:

• Analysis of 500 biosynthetic gene clusters identified 131 novel pNPs.
• Fifty-one diverse pNPs were successfully synthesized.
• Fourteen synthesized pNPs exhibited significant antibiotic activity, including against multidrug-resistant Gram-negative bacteria.

Conclusions:

• The SNaPP method effectively accelerates the discovery of bioactive molecules by merging computational predictions with synthetic chemistry.
• This approach holds promise for identifying novel peptide-based therapeutics, particularly antibiotics to address the challenge of antimicrobial resistance.