Selective inhibition of Helicobacter pylori methionine aminopeptidase by azaindole hydroxamic acid derivatives: Design, synthesis, in vitro biochemical and structural studies.

Anti-Bacterial Agents / chemistry Bacterial Proteins / antagonists & inhibitors Drug Design Enzyme Inhibitors / chemistry Helicobacter Infections / drug therapy Helicobacter pylori / chemistry Humans Hydroxamic Acids / chemistry Indoles / chemistry Methionyl Aminopeptidases / antagonists & inhibitors Models, Molecular
Azaindole Helicobacter pylori Hydroxamic acid Methionine aminopeptidase Selective inhibition

Journal

Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703

Informations de publication

Date de publication:
10 2021
Historique:
received: 01 03 2021
revised: 04 06 2021
accepted: 14 07 2021
pubmed: 31 7 2021
medline: 18 12 2021
entrez: 30 7 2021
Statut: ppublish

Résumé

Methionine aminopeptidases (MetAPs) are an important class of enzymes that work co-translationally for the removal of initiator methionine. Chemical inhibition or gene knockdown is lethal to the microbes suggesting that they can be used as antibiotic targets. However, sequence and structural similarity between the microbial and host MetAPs has been a challenge in the identification of selective inhibitors. In this study, we have analyzed several thousands of MetAP sequences and established a pattern of variation in the S1 pocket of the enzyme. Based on this knowledge, we have designed a library of 17 azaindole based hydroxamic acid derivatives which selectively inhibited the MetAP from H. pylori compared to the human counterpart. Structural studies provided the molecular basis for the selectivity.

Identifiants

DOI: 10.1016/j.bioorg.2021.105185 PMID: 34329997
pubmed: 34329997
pii: S0045-2068(21)00562-9
doi: 10.1016/j.bioorg.2021.105185
pii:
doi:

Substances chimiques

Anti-Bacterial Agents 0
Bacterial Proteins 0
Enzyme Inhibitors 0
Hydroxamic Acids 0
Indoles 0
Methionyl Aminopeptidases EC 3.4.11.18

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

105185

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Auteurs

Sandeepchowdary Bala (S)

Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201 002, India.

Kalisha Vali Yellamanda (KV)

Department of Chemistry, School of Science, GITAM Deemed to be University, Hyderabad 502 102, Telangana, India.

Anilkumar Kadari (A)

Department of Chemistry, School of Science, GITAM Deemed to be University, Hyderabad 502 102, Telangana, India.

Venkata S U Ravinuthala (VSU)

Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India.

Bhavita Kattula (B)

Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201 002, India.

Om V Singh (OV)

Department of Chemistry, School of Science, GITAM Deemed to be University, Hyderabad 502 102, Telangana, India.

Rambabu Gundla (R)

Department of Chemistry, School of Science, GITAM Deemed to be University, Hyderabad 502 102, Telangana, India. Electronic address: rgundla@gmail.com.

Anthony Addlagatta (A)

Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201 002, India. Electronic address: anthony@csiriict.in.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines bactériennes › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Conception de médicament › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Infections bactériennes › Infections bactériennes à Gram négatif › Infections à Helicobacter › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Bactéries › Proteobacteria › Epsilonproteobacteria › Campylobacterales › Helicobacteraceae › Helicobacter › Helicobacter pylori › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Composés chimiques organiques › Acides carboxyliques › Hydroxyacides › Acides hydroxamiques › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indoles › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Exopeptidases › Aminopeptidases › Methionyl aminopeptidases › Selective inhibition of Helicobacter pylori...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Selective inhibition of Helicobacter pylori...