5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein.
Fiche publication
Date publication
mai 2020
Journal
ACS medicinal chemistry letters
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MELY Yves
Tous les auteurs :
Malancona S, Mori M, Fezzardi P, Santoriello M, Basta A, Nibbio M, Kovalenko L, Speziale R, Battista MR, Cellucci A, Gennari N, Monteagudo E, Di Marco A, Giannini A, Sharma R, Pires M, Real E, Zazzi M, Dasso Lang MC, De Forni D, Saladini F, Mely Y, Summa V, Harper S, Botta M
Lien Pubmed
Résumé
The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the 5-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound , showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.
Référence
ACS Med Chem Lett. 2020 May 14;11(5):766-772