5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein
| Autor: | Maria Rosaria Battista, Rajhans Sharma, Yves Mély, Marisabella Santoriello, Edith Monteagudo, Paola Fezzardi, Eleonore Real, Maurizio Zazzi, Vincenzo Summa, Mattia Mori, Maria Chiara Dasso Lang, Steven J. Harper, Savina Malancona, Antonella Cellucci, Manuel Pires, Martina Nibbio, Maurizio Botta, Roberto Speziale, Andreina Basta, Nadia Gennari, Francesco Saladini, Davide De Forni, Annalise Di Marco, Alessia Giannini, Lesia Kovalenko |
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| Přispěvatelé: | 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. |
| Rok vydání: | 2020 |
| Předmět: |
Nucleocapsid protein
Scaffold drug resistance 010405 organic chemistry antiretroviral Organic Chemistry HIV RNA-binding protein Drug resistance 01 natural sciences Biochemistry 0104 chemical sciences 3. Good health Conserved sequence Nordihydroguaiaretic acid 010404 medicinal & biomolecular chemistry chemistry.chemical_compound NC inhibitor chemistry Viral replication Drug Discovery DNA dihydroxypyrimidine ADME |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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