Cyclotheonellazoles D-I, Potent Elastase Inhibitory Thiazole-Containing Cyclic Peptides from Theonella sp. (2131)

Area of Science:

• Marine Natural Products Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Marine sponges are a rich source of structurally diverse bioactive compounds.
• Cyclic peptides, particularly those containing thiazole rings, often exhibit significant biological activities.
• Proteases like elastase and SARS-CoV-2 3CLpro are important therapeutic targets.

Purpose of the Study:

• To isolate and characterize new thiazole-containing cyclic peptides from the marine sponge *Theonella* sp.
• To evaluate the protease inhibitory activities of these novel compounds and related natural products.
• To assess the cytotoxic effects of the isolated peptides on human cancer cell lines.

Main Methods:

• Isolation of compounds using chromatographic techniques.
• Structure elucidation via comprehensive spectroscopic analyses (1D/2D NMR, MS) and chemical derivatization.
• Computational methods including time-dependent density functional theory (TDDFT) for ECD data comparison.
• Enzyme inhibition assays against elastase, chymotrypsin, and SARS-CoV-2 3CLpro.
• In vitro cytotoxicity assays on human cancer cell lines.

Main Results:

• Six new cyclotheonellazoles (D-I) and two reisolated keramamides (A and L) were obtained.
• Cyclotheonellazoles D-I and keramamide A demonstrated potent nanomolar inhibition of elastase.
• Keramamide A also exhibited moderate inhibition against chymotrypsin and SARS-CoV-2 3CLpro.
• Cyclotheonellazoles D-E showed no cytotoxicity against breast, ovarian, and colon cancer cells.

Conclusions:

• The study successfully identified novel cyclic peptides with significant elastase inhibitory activity.
• These findings highlight the potential of marine-derived thiazole peptides as leads for protease inhibitor drug discovery.
• The isolated compounds, particularly cyclotheonellazoles, represent promising scaffolds for further medicinal chemistry exploration.