New inhibitors of microbial M1 metallo-aminopeptidases obtained by chemical synthesis

Authors

  • Jorge González Bacerio Unversidad de La Habana
  • Yanira Méndez Gómez Centro de Estudio de Productos Naturales, Facultad de Química, Universidad de La Habana
  • Daniel García Rivera Centro de Estudio de Productos Naturales, Facultad de Química, Universidad de La Habana
  • Maday Alonso del Rivero Antigua Facultad de Biología, Universidad de La Habana
  • Marcos Gazarini Dutra Departamento de Biofísica, Universidad Federal de Sao Paulo
  • Maria de los Ángeles Chavez Planes Facultad de Biología, Universidad de La Habana
  • Adriana K Carmona Departamento de Biofísica, Universidad Federal de Sao Paulo

Keywords:

antibacterial and antimalarial agents, microbial M1 aminopeptidases, synthetic aminopeptidase inhibitors, Ugi-multicomponent reaction

Abstract

Introduction. Infections by bacteria resistant to conventional antibiotics are a worldwide health problem. Likewise, the parasite causal agent of malaria, main tropical parasitic disease, has developed resistance to the traditional drugs. In this sense, aminopeptidasese PepN, from the bacterium Escherichia coli, and PfA-M1, from the Plasmodium falciparum parasite, are new targets in these sicknesses. The objective of this work was the identification of synthetic inhibitors of ePepN and PfA-M1, with potentialities as antibacterial and antimalarial agents.
Methods. Using two multicomponent Ugi-reactions, two libraries of 33 bestatin- and actinonin-based peptidomimetics were synthesized and evaluated against PfA-M1. In addition, 22 tetrazole-peptidomimetics were synthesized and evaluated against ePepN.
Results. Three tetrazoles (YTE003, YTE007, YTE008) were identified as potent and selective ePepN inhibitors, regarding porcine M1 aminopeptidase (pAPN). YTE003 shows in vitro antibacterial activity, which supports its potential as leader compound in the field of antibacterial agents. Toward PfA-M1, compound KBE009 was identified as a potent inhibitor, with in vitro antimalarial activity, that does not inhibit pAPN at concentrations of therapeutic relevance, and it is not cytotoxic up to 200 μmol/L against the human HUVEC cell line. It was found that KBE009 inhibits AP activity in the whole and isolated parasite in the same order of magnitude as its in vitro antimalarial activity. These properties lead into considering the peptidomimetic a promising molecule as a lead compound against malaria.

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Author Biography

Jorge González Bacerio, Unversidad de La Habana

Jefe de Departamento de Bioquímica, Fcaultad de Biología

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Published

2020-09-13

How to Cite

González Bacerio, J., Méndez Gómez, Y., García Rivera, D., Alonso del Rivero Antigua, M., Gazarini Dutra, M., Chavez Planes, M. de los Ángeles, & Carmona, A. K. (2020). New inhibitors of microbial M1 metallo-aminopeptidases obtained by chemical synthesis. Anales De La Academia De Ciencias De Cuba, 10(3), e814. Retrieved from https://revistaccuba.sld.cu/index.php/revacc/article/view/814

Issue

Vol. 10 No. 3 (2020): septiembre-diciembre

Section

Natural and Exact Sciences

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