Bioactive Peptide Natural Products as Lead Structures for Medicinal Use

Area of Science:

• Natural Product Chemistry
• Microbiology
• Medicinal Chemistry

Background:

• Microorganisms are a rich source of novel peptide natural products with significant therapeutic potential, particularly as anti-infective agents.
• Peptide natural products are broadly classified into ribosomally synthesized and post-translationally modified peptides (RiPPs) and those synthesized by multimodular nonribosomal peptide synthetases (NRPSs).
• The discovery and development of these compounds involve interdisciplinary efforts spanning biology, chemistry, and medicine.

Purpose of the Study:

• To highlight recent discoveries, approaches, and research on RiPPs and NRPSs from bacteria and fungi.
• To explore the potential of labyrinthopeptins, albicidin, and cyclodepsipeptides as sources for new drug candidates.
• To investigate structure-activity relationships and synthetic strategies for bioactive peptides.

Main Methods:

• Classical screening, in silico prediction, and genome mining for natural product discovery.
• Biochemical studies, site-directed mutagenesis, and chemoenzymatic approaches to elucidate biosynthetic pathways.
• Total synthesis, heterologous expression, and medicinal chemistry for analog generation and drug development.

Main Results:

• Labyrinthopeptins (class III lanthipeptides) exhibit antiallodynic and antiviral activities, with ongoing research into their biosynthesis and analog generation.
• Albicidin, a potent inhibitor of gyrase, shows strong activity against Gram-negative bacteria, with chemical synthesis enabling derivative exploration for anti-Gram-negative drug development.
• Cyclodepsipeptides, including marketed drugs, possess antibacterial, antifungal, insecticidal, and anthelmintic properties, offering lead structures for further drug development.

Conclusions:

• Microbial peptide natural products, including RiPPs and NRPSs, represent a vital resource for discovering new drugs, especially anti-infectives.
• Advanced methodologies in genomics, bioinformatics, and synthetic chemistry are accelerating the identification and development of novel peptide-based therapeutics.
• Future research focusing on reprogramming NRPSs and exploring untapped structural spaces holds promise for identifying new drug candidates with enhanced bioactivities.