Disulfide bridge-targeted metabolome mining unravels an antiparkinsonian peptide.
10.1016/j.apsb.2023.09.006
- Author:
Zhiwu TONG
1
;
Xiahong XIE
2
;
Huiming GE
1
;
Ruihua JIAO
1
;
Tingting WANG
1
;
Xincun WANG
3
;
Wenying ZHUANG
3
;
Gang HU
2
;
Renxiang TAN
1
Author Information
1. State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, School of Life Sciences, Nanjing University, Nanjing 210023, China.
2. State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
3. Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
- Publication Type:Journal Article
- Keywords:
Acalitide;
Antiparkinsonian;
Biosynthesis;
Fungal RiPPs;
Macrocyclic peptide
- From:
Acta Pharmaceutica Sinica B
2024;14(2):881-892
- CountryChina
- Language:English
-
Abstract:
Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics, thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials. However, the success rate is decreasing, presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely 'overlooked' during the characterization effort. Here, we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP (ribosomally synthesized and post-translationally modified peptide), named acalitide, by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules. Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease (AcaB)-catalyzed lactamization of AcaA, an unprecedented precursor peptide. Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy. Taken together, the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson's disease that is globally prevailing in an alarming manner.
