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 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.
5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein / Malancona, S.; Mori, M.; Fezzardi, P.; Santoriello, M.; Basta, A.; Nibbio, M.; Kovalenko, L.; Speziale, R.; Battista, M. R.; Cellucci, A.; Gennari, N.; Monteagudo, E.; Di Marco, A.; Giannini, A.; Sharma, R.; Pires, M.; Real, E.; Zazzi, M.; Dasso Lang, M. C.; De Forni, D.; Saladini, F.; Mely, Y.; Summa, V.; Harper, S.; Botta, M.. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 11:5(2020), pp. 766-772. [10.1021/acsmedchemlett.9b00608]
5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein
Summa V.;
2020
Abstract
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 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
