Microbially Guided Discovery and Biosynthesis of Biologically Active Natural Products.
ACS Synth Biol
; 10(6): 1505-1519, 2021 06 18.
Article
em En
| MEDLINE
| ID: mdl-33988973
ABSTRACT
The design of small molecules that inhibit disease-relevant proteins represents a longstanding challenge of medicinal chemistry. Here, we describe an approach for encoding this challenge-the inhibition of a human drug target-into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active natural products. This approach identified two previously unknown terpenoid inhibitors of protein tyrosine phosphatase 1B (PTP1B), an elusive therapeutic target for the treatment of diabetes and cancer. Both inhibitors appear to target an allosteric site, which confers selectivity, and can inhibit PTP1B in living cells. A screen of 24 uncharacterized terpene synthases from a pool of 4464 genes uncovered additional hits, demonstrating a scalable discovery approach, and the incorporation of different PTPs into the microbial host yielded alternative PTP-specific detection systems. Findings illustrate the potential for using microbes to discover and build natural products that exhibit precisely defined biochemical activities yet possess unanticipated structures and/or binding sites.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Terpenos
/
Produtos Biológicos
/
Inibidores Enzimáticos
/
Escherichia coli
/
Proteína Tirosina Fosfatase não Receptora Tipo 1
/
Descoberta de Drogas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
ACS Synth Biol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos