5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

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.

Figure 1

NC inhibitors based on catechol template 1 and 2. 5,6-Didihydroxypyrimidine 3 as catechol replacement and hit compound 4 active in the NC-inhibition assay. Raltegravir, first in class HIV integrase inhibitor.

Figure 2

Dihydroxypyrimidine core modifications leading to lack of NC inhibition.

Figure 3

Predicted binding mode of 28 within the hydrophobic pocket of the NC. The protein is shown as a green cartoon. Residues within 5 Å from the ligands are shown as lines and are labeled. Compound 28 is shown as yellow sticks. H-bond interactions are highlighted by black dashed lines.