Cargando…

Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster

Rare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Chunshun, Hu, Yifei, Wu, Xiaohua, Stumpf, Spencer D., Qi, Yunci, D’Alessandro, John M., Nepal, Keshav K., Sarotti, Ariel M., Cao, Shugeng, Blodgett, Joshua A. V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169926/
https://www.ncbi.nlm.nih.gov/pubmed/35439047
http://dx.doi.org/10.1073/pnas.2117941119
_version_ 1784721302150447104
author Li, Chunshun
Hu, Yifei
Wu, Xiaohua
Stumpf, Spencer D.
Qi, Yunci
D’Alessandro, John M.
Nepal, Keshav K.
Sarotti, Ariel M.
Cao, Shugeng
Blodgett, Joshua A. V.
author_facet Li, Chunshun
Hu, Yifei
Wu, Xiaohua
Stumpf, Spencer D.
Qi, Yunci
D’Alessandro, John M.
Nepal, Keshav K.
Sarotti, Ariel M.
Cao, Shugeng
Blodgett, Joshua A. V.
author_sort Li, Chunshun
collection PubMed
description Rare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate building blocks resulted in the discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, petrichorins A and B. Petrichorin B is a symmetric homodimer similar to the known compound chloptosin, but petrichorin A is unique among known piperazyl cyclopeptides because it is an asymmetric heterodimer. Due to the structural complexity of petrichorin A, solving its structure required a combination of several standard chemical methods plus in silico modeling, strain mutagenesis, and solving the structure of its biosynthetic intermediate petrichorin C for confident assignment. Furthermore, we found that the piperazyl cyclopeptides comprising each half of the petrichorin A heterodimer are made via two distinct nonribosomal peptide synthetase (NRPS) assembly lines, and the responsible NRPS enzymes are encoded within a contiguous biosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscuous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl production, petrichorins A and B exhibited potent in vitro activity against A2780 human ovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkat human T lymphocyte cell lines with IC(50) values at low nM levels. Cyclic piperazyl peptides and their crosslinked derivatives are interesting drug leads, and our findings highlight the potential for heterodimeric bicyclic peptides such as petrichorin A for inclusion in future pharmaceutical design and discovery programs.
format Online
Article
Text
id pubmed-9169926
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-91699262022-07-22 Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster Li, Chunshun Hu, Yifei Wu, Xiaohua Stumpf, Spencer D. Qi, Yunci D’Alessandro, John M. Nepal, Keshav K. Sarotti, Ariel M. Cao, Shugeng Blodgett, Joshua A. V. Proc Natl Acad Sci U S A Biological Sciences Rare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate building blocks resulted in the discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, petrichorins A and B. Petrichorin B is a symmetric homodimer similar to the known compound chloptosin, but petrichorin A is unique among known piperazyl cyclopeptides because it is an asymmetric heterodimer. Due to the structural complexity of petrichorin A, solving its structure required a combination of several standard chemical methods plus in silico modeling, strain mutagenesis, and solving the structure of its biosynthetic intermediate petrichorin C for confident assignment. Furthermore, we found that the piperazyl cyclopeptides comprising each half of the petrichorin A heterodimer are made via two distinct nonribosomal peptide synthetase (NRPS) assembly lines, and the responsible NRPS enzymes are encoded within a contiguous biosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscuous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl production, petrichorins A and B exhibited potent in vitro activity against A2780 human ovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkat human T lymphocyte cell lines with IC(50) values at low nM levels. Cyclic piperazyl peptides and their crosslinked derivatives are interesting drug leads, and our findings highlight the potential for heterodimeric bicyclic peptides such as petrichorin A for inclusion in future pharmaceutical design and discovery programs. National Academy of Sciences 2022-04-19 2022-04-26 /pmc/articles/PMC9169926/ /pubmed/35439047 http://dx.doi.org/10.1073/pnas.2117941119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Li, Chunshun
Hu, Yifei
Wu, Xiaohua
Stumpf, Spencer D.
Qi, Yunci
D’Alessandro, John M.
Nepal, Keshav K.
Sarotti, Ariel M.
Cao, Shugeng
Blodgett, Joshua A. V.
Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
title Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
title_full Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
title_fullStr Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
title_full_unstemmed Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
title_short Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
title_sort discovery of unusual dimeric piperazyl cyclopeptides encoded by a lentzea flaviverrucosa dsm 44664 biosynthetic supercluster
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169926/
https://www.ncbi.nlm.nih.gov/pubmed/35439047
http://dx.doi.org/10.1073/pnas.2117941119
work_keys_str_mv AT lichunshun discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT huyifei discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT wuxiaohua discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT stumpfspencerd discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT qiyunci discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT dalessandrojohnm discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT nepalkeshavk discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT sarottiarielm discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT caoshugeng discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster
AT blodgettjoshuaav discoveryofunusualdimericpiperazylcyclopeptidesencodedbyalentzeaflaviverrucosadsm44664biosyntheticsupercluster