Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure.

Abstract

BACKGROUND:

Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent.

METHODS:

Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies.

RESULTS:

In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB).

CONCLUSIONS:

Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aβ levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

• Authors: Daniel Fabio Kawano, Marcelo Rodrigues de Carvalho, Mauricio Ferreira Marcondes Machado, Adriana Karaoglanovic Carmona, Gilberto Ubida Leite Braga, Ivone Carvalho
• Journal: Current pharmaceutical design (Curr Pharm Des) Vol. 24 Issue 17 Pg. 1899-1904 ( 2018) ISSN: 1873-4286 [Electronic] United Arab Emirates
• PMID: 29766796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Protease Inhibitors
• Tyrosine
• tyrosine betaine
• Neprilysin

Topics

• Crystallography, X-Ray
• Heart Failure (drug therapy, metabolism)
• Humans
• Models, Molecular
• Molecular Structure
• Neprilysin (antagonists & inhibitors, metabolism)
• Protease Inhibitors (chemical synthesis, chemistry, pharmacology)
• Tyrosine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)