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

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

Volume: 24 Issue: 17

Author(s): Daniel Fabio Kawano*, Marcelo Rodrigues de Carvalho, Mauricio Ferreira Marcondes Machado, Adriana Karaoglanovic Carmona, Gilberto Ubida Leite Braga and Ivone Carvalho

Affiliation:

• Faculty of Pharmaceutical Sciences, University of Campinas - UNICAMP, Rua Candido Portinari 200, 13083-871 Campinas-SP,Brazil

Keywords: Neprilysin, heart failure, tyrosine betaine, fungal metabolites, Metarhizium spp, blood brain barrier.

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.

Cite this article as:

Kawano Fabio Daniel *, de Carvalho Rodrigues Marcelo , Machado Ferreira Marcondes Mauricio , Carmona Karaoglanovic Adriana , Braga Ubida Leite Gilberto and Carvalho Ivone , Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure, Current Pharmaceutical Design 2018; 24 (17) . https://dx.doi.org/10.2174/1381612824666180515114236