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| Main Authors: | , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Journal of natural products
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41105455/ |
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Table of Contents:
- Biosynthesis, Chemical Synthesis, and Pharmacological Evaluation of Lyngbyapeptin A as a GPCR Antagonist of Motilin, Cannabinoid, and Amylin Receptors. Pham, Tam H D Chen, Manyun Liu, Jie Chen, Qi-Yin Seabra, Gustavo Paul, Valerie J Donia, Mohamed S Bruner, Steven D Ding, Yousong Luesch, Hendrik Humans Molecular Structure Receptors, G-Protein-Coupled Cyanobacteria Receptors, Gastrointestinal Hormone Receptors, Cannabinoid Multigene Family Lyngbya Toxins Papua New Guinea Oligopeptides Lyngbyapeptin A () is a linear modified tetrapeptide originally isolated from the marine cyanobacterium in Papua New Guinea and Guam. In previous research, did not show significant cytotoxicity but was not rigorously investigated due to insufficient material and the propensity of the ()-3-methoxy-2-butenoyl moiety to undergo conversion into a ketone, preventing further biological testing. In this study, we report the identification and characterization of the biosynthetic gene cluster (BGC) of from a collection. The first total synthesis of , of its keto analogue named 5-desmethyl-lyngbyapeptin A (), and of acrylamide analogue was also achieved by convergent liquid-phase peptide synthesis. Compounds - were subjected to functional GPCR target-based β-arrestin screens to identify their activity profiles. Four GPCRs, including amylin receptor 2 (CALCR-RAMP2), motilin receptor (MLNR), and cannabinoid receptors CNR1 and CNR2, were antagonized by , supported by secondary functional and binding assays. These receptors were also modulated by and but to a lesser extent, with 2- to 12-fold decrease in potency, demonstrating the role of the ()-3-methoxy-2-butenoyl moiety in contributing to the GPCR modulating activity. The binding modes of to the GPCR hits were further investigated using molecular modeling.