Cargando…
Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase
Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753110/ https://www.ncbi.nlm.nih.gov/pubmed/31537874 http://dx.doi.org/10.1038/s41598-019-49984-3 |
_version_ | 1783452829290070016 |
---|---|
author | Sakamoto, Yasumitsu Suzuki, Yoshiyuki Nakamura, Akihiro Watanabe, Yurie Sekiya, Mizuki Roppongi, Saori Kushibiki, Chisato Iizuka, Ippei Tani, Osamu Sakashita, Hitoshi Inaka, Koji Tanaka, Hiroaki Yamada, Mitsugu Ohta, Kazunori Honma, Nobuyuki Shida, Yosuke Ogasawara, Wataru Nakanishi-Matsui, Mayumi Nonaka, Takamasa Gouda, Hiroaki Tanaka, Nobutada |
author_facet | Sakamoto, Yasumitsu Suzuki, Yoshiyuki Nakamura, Akihiro Watanabe, Yurie Sekiya, Mizuki Roppongi, Saori Kushibiki, Chisato Iizuka, Ippei Tani, Osamu Sakashita, Hitoshi Inaka, Koji Tanaka, Hiroaki Yamada, Mitsugu Ohta, Kazunori Honma, Nobuyuki Shida, Yosuke Ogasawara, Wataru Nakanishi-Matsui, Mayumi Nonaka, Takamasa Gouda, Hiroaki Tanaka, Nobutada |
author_sort | Sakamoto, Yasumitsu |
collection | PubMed |
description | Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in silico inhibitor screening. The screening resulted in an active compound SH-5, the first nonpeptidyl inhibitor of S46 peptidases. SH-5 and a lipophilic analog of SH-5 showed a dose-dependent inhibitory effect against the growth of P. gingivalis. The binding mode of SH-5 was confirmed by crystal structure analysis. Thus, these compounds could be lead structures for the development of selective inhibitors of PgDPP11. |
format | Online Article Text |
id | pubmed-6753110 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67531102019-10-01 Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase Sakamoto, Yasumitsu Suzuki, Yoshiyuki Nakamura, Akihiro Watanabe, Yurie Sekiya, Mizuki Roppongi, Saori Kushibiki, Chisato Iizuka, Ippei Tani, Osamu Sakashita, Hitoshi Inaka, Koji Tanaka, Hiroaki Yamada, Mitsugu Ohta, Kazunori Honma, Nobuyuki Shida, Yosuke Ogasawara, Wataru Nakanishi-Matsui, Mayumi Nonaka, Takamasa Gouda, Hiroaki Tanaka, Nobutada Sci Rep Article Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in silico inhibitor screening. The screening resulted in an active compound SH-5, the first nonpeptidyl inhibitor of S46 peptidases. SH-5 and a lipophilic analog of SH-5 showed a dose-dependent inhibitory effect against the growth of P. gingivalis. The binding mode of SH-5 was confirmed by crystal structure analysis. Thus, these compounds could be lead structures for the development of selective inhibitors of PgDPP11. Nature Publishing Group UK 2019-09-19 /pmc/articles/PMC6753110/ /pubmed/31537874 http://dx.doi.org/10.1038/s41598-019-49984-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Sakamoto, Yasumitsu Suzuki, Yoshiyuki Nakamura, Akihiro Watanabe, Yurie Sekiya, Mizuki Roppongi, Saori Kushibiki, Chisato Iizuka, Ippei Tani, Osamu Sakashita, Hitoshi Inaka, Koji Tanaka, Hiroaki Yamada, Mitsugu Ohta, Kazunori Honma, Nobuyuki Shida, Yosuke Ogasawara, Wataru Nakanishi-Matsui, Mayumi Nonaka, Takamasa Gouda, Hiroaki Tanaka, Nobutada Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase |
title | Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase |
title_full | Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase |
title_fullStr | Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase |
title_full_unstemmed | Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase |
title_short | Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase |
title_sort | fragment-based discovery of the first nonpeptidyl inhibitor of an s46 family peptidase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753110/ https://www.ncbi.nlm.nih.gov/pubmed/31537874 http://dx.doi.org/10.1038/s41598-019-49984-3 |
work_keys_str_mv | AT sakamotoyasumitsu fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT suzukiyoshiyuki fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT nakamuraakihiro fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT watanabeyurie fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT sekiyamizuki fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT roppongisaori fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT kushibikichisato fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT iizukaippei fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT taniosamu fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT sakashitahitoshi fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT inakakoji fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT tanakahiroaki fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT yamadamitsugu fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT ohtakazunori fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT honmanobuyuki fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT shidayosuke fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT ogasawarawataru fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT nakanishimatsuimayumi fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT nonakatakamasa fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT goudahiroaki fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase AT tanakanobutada fragmentbaseddiscoveryofthefirstnonpeptidylinhibitorofans46familypeptidase |