The topoisomerase II beta-kinase associated with HIV-1 is a potential target for pyridine-bischalcones' anti-HIV-1 activity

Topoisomerase II (TopoII) is a critical component of HIV-1 integration, proviral DNA synthesis, and reverse transcription. During HIV-1 infection, the TopoII beta kinase (TopoII beta KHIV-1) phosphorylates TopoII beta. Our earlier research demonstrated that the pyridine scaffold has potent anti-HIV-1 activity by specifically inhibiting TopoII beta KHIV1 activity. 3D QSAR results showed the presence of molecular features for interaction with TopoII beta KHIV-1 requiring chemically induced proximity for potential interaction. In this study, the chalcone and methyl groups were added to the pyridine scaffold's core to achieve the desired proximity length between the pyridine scaffold and charged centers, which resulted in an inhibitory activity against TopoII beta KHIV-1 and viral replication. According to the findings, the TopoII beta KHIV-1 activity was inhibited by the inclusion of the pyridine scaffold with the chalcone group, leading to better anti-HIV-1 activity. The water-soluble methylated pyridinium chalcones' showed significant TopoII beta KHIV- 1 antagonism, anti-HIV-1 activity (from IC50 > 500 nM to ID50 25 nM), and reduced cytotoxicity (CC50 = 2 mM). These activities could be associated with the charge on the pyridine and extended proximity. Therefore, it is clear that within the scope of this work, altering the proximity length and charge centers of pyridine molecules are critical for the design and development of effective anti-HIV-1 leads, specifically targeting TopoII beta KHIV-1.

Automated summary

This study found that by adding chalcone and methyl groups to the pyridine scaffold, the desired proximity length between the pyridine scaffold and charged centers can be achieved, resulting in inhibitory activity against TopoIIbetaKHIV-1 and viral replication.