Autor: Dak, M.; Šlachtová, V.; Šebela, M.; Bazgier, V.; Berka, K.; Smiejkowska, N.; Oorts, L.; Cappoen, D.; Brulíková, L.*
Název práce v češtině: Nové heterocyklické hydroxamáty jako inhibitory mykobakteriální metloproteázy Zmp1
Název práce v angličtině: Novel heterocyclic hydroxamates as inhibitors of the mycobacterial zinc metalloprotease Zmp1 to probe its mechanism of function
Studentská publikace: ne
Klíčová slova v češtině: Mycobacterium tuberculosis, virulentní faktor Zmp1, hydroxamát, thiazolidindion, indol, pyrrol.
Klíčová slova v angličtině: Mycobacterium tuberculosis, virulence factor Zmp1, hydroxamate, thiazolidinedione, indole, pyrrole.
Abstrakt česky: Mykobakteriální Zmp1 je považována za enzym nutný k přežití bakterie uvnitř makrofágu. Ačkoliv přesný mechanismus není stále objasněn. V předkládaném článku je popsána syntéza nových inhibitorů Zmp1 a jejich biologická aktivita.
Abstrakt anglicky: Mycobacterial zinc metalloprotease-1 (Zmp1) is an essential enzyme for intracellular survival and pathogenicity of Mycobacterium tuberculosis. However, the exact mechanism of function of this enzyme remains unclear. This paper examines the effect of novel organic molecules on the inhibition of Zmp1. We followed our previous results and synthesised three libraries of new hydroxamates. All compounds were studied for their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis by MALDI-TOF MS. Furthermore, a macrophage infection assay was performed to evaluate intracellular antimycobacterial activity. In the whole-cell assay, no direct activity of synthesised heterocyclic hydroxamates was observed against Mycobacterium tuberculosis and Mycobacterium bovis. No acute cellular toxicity was observed against the murine RAW 264.7 macrophage cell line and human MRC-5 lung fibroblast cell line. However, thiazolidinediones 2 showed the dose-dependent inhibition of intracellular survival of Mycobacterium tuberculosis H37Ra. The inhibition was structure-dependent, with the most active derivative 2f inducing an 83.2% reduction of bacterial survival within the macrophage host cell. The promising biological activity confirmed thiazolidinediones 2 as Zmp1 inhibitors that can be used as tool compounds for further exploration of the role of Zmp1 for in vivo pathogenicity. In the long run, thiazolidinediones 2 show the potential to act as a scaffold for Zmp1 inhibitors to target intracellular Mtb as a novel tuberculosis treatment strategy.
Jazyk v originále: angličtina
Název časopisu: Eur. J. Med. Chem.
Rok: 2022
Svazek (ročník): 244
Číslo časopisu v rámci uvedeného svazku: –
Strana od-do: 114831 (1-15)
Impact factor: 7.088
Q1: ne

ISSN časopisu: 0223-5234
Vydavatel: Elsevier
Způsob financování: JG_2019_002; G066619; LM2018131
DOI: 10.1016/j.ejmech.2022.114831