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5,6-Dihydroxypyrimidine Scaffold to Target HIV‑1 Nucleocapsid Protein
journal contribution
posted on 2020-03-23, 15:06 authored by Savina Malancona, Mattia Mori, Paola Fezzardi, Marisabella Santoriello, Andreina Basta, Martina Nibbio, Lesia Kovalenko, Roberto Speziale, Maria Rosaria Battista, Antonella Cellucci, Nadia Gennari, Edith Monteagudo, Annalise Di Marco, Alessia Giannini, Rajhans Sharma, Manuel Pires, Eleonore Real, Maurizio Zazzi, Maria Chiara Dasso Lang, Davide De Forni, Francesco Saladini, Yves Mely, Vincenzo Summa, Steven Harper, Maurizio BottaThe 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 1 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 28, showing improved NC inhibition and antiviral
activity as well as good ADME and PK properties.
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optimized analogsRNA binding proteincatechol moietiesDRPK propertiesantiretroviral therapyADMEsuboptimal drug-like propertiesvalidation effortsDNANC inhibitionanti-HIV agentsnordihydroguaiaretic acid 1 actsbioisosteric catechol replacement approachNC inhibitordrug resistanceNC inhibitorsHAARTcompound 28
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