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Biosynthesis of rumbrins and inspiration for discovery of HIV inhibitors.
- Source :
- Acta Pharmaceutica Sinica B; Nov2022, Vol. 12 Issue 11, p4193-4203, 11p
- Publication Year :
- 2022
-
Abstract
- Investigation on how nature produces natural compounds with chemical and biological diversity at the genetic level offers inspiration for the discovery of new natural products and even their biological targets. The polyketide rumbrin (1) is a lipid peroxide production and calcium accumulation inhibitor, which contains a chlorinated pyrrole moiety that is a rare chemical feature in fungal natural products. Here, we identify the biosynthetic gene cluster (BGC) rum of 1 and its isomer 12 E -rumbrin (2) from Auxarthron umbrinum DSM3193, and elucidate their biosynthetic pathway based on heterologous expression, chemical complementation, and isotopic labeling. We show that rumbrins are assembled by a highly reducing polyketide synthase (HRPKS) that uniquely incorporates a proline-derived pyrrolyl-CoA starer unit, and followed by methylation and chlorination. Sequent precursor-directed biosynthesis was able to yield a group of rumbrin analogues. Remarkably, inspired by the presence of a human immunodeficiency virus (HIV)-Nef-associated gene in the rum cluster, we predicted and pharmacologically demonstrated rumbrins as potent inhibitors of HIV at the nanomolar level. This work enriches the recognition of unconventional starter units of fungal PKSs and provides a new strategy for genome mining-guided drug discovery. We reconstituted the biosynthesis of rumbrins, identified a new starter unit of PKS, and obtained nine rumbrin analogues. Guided by rumB , we predicted and pharmacologically demonstrated rumbrins as anti-HIV agents. [Display omitted] [ABSTRACT FROM AUTHOR]
- Subjects :
- POLYKETIDES
BIOSYNTHESIS
DRUG discovery
ANTI-HIV agents
HIV
DRUG target
Subjects
Details
- Language :
- English
- ISSN :
- 22113835
- Volume :
- 12
- Issue :
- 11
- Database :
- Supplemental Index
- Journal :
- Acta Pharmaceutica Sinica B
- Publication Type :
- Academic Journal
- Accession number :
- 159994263
- Full Text :
- https://doi.org/10.1016/j.apsb.2022.02.005