Synthesis and Evaluation of Bifunctional Aminothiazoles as Antiretrovirals Targeting the HIV-1 Nucleocapsid Protein.
Fiche publication
Date publication
avril 2019
Journal
ACS medicinal chemistry letters
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MELY Yves
Tous les auteurs :
Mori M, Dasso Lang MC, Saladini F, Palombi N, Kovalenko L, De Forni D, Poddesu B, Friggeri L, Giannini A, Malancona S, Summa V, Zazzi M, Mely Y, Botta M
Lien Pubmed
Résumé
Small molecule inhibitors of the HIV-1 nucleocapsid protein (NC) are considered as promising agents in the treatment of HIV/AIDS. In an effort to exploit the privileged 2-amino-4-phenylthiazole moiety in NC inhibition, here we conceived, synthesized, and tested 18 NC inhibitors (NCIs) bearing a double functionalization. In these NCIs, one part of the molecule is deputed to interact noncovalently with the NC hydrophobic pocket, while the second portion is designed to interact with the N-terminal domain of NC. This binding hypothesis was verified by molecular dynamics simulations, while the linkage between these two pharmacophores was found to enhance antiretroviral activity both on the wild-type virus and on HIV-1 strains with resistance to currently licensed drugs. The two most interesting compounds and showed no cytotoxicity, thus becoming valuable leads for further investigations.
Référence
ACS Med Chem Lett. 2019 Apr 11;10(4):463-468