HIV integrase inhibitors (INi) are among the most effective agents used in the treatment of HIV infection. They target HIV IN, the enzyme that inserts the viral genome into the chromosomes of the host cells. IN binds to sequences, flanking the viral DNA called LTR (Long Terminal Repeats) and cleaves specific phosphodiester bonds at 3′ ends (the 3′ processing reaction).
In earlier studies, β-ketoenol structure and coplanar aromatic rings have been recognised as pharmacophores of IN inhibitors, and some flavonoids, lignans and phenylpropanoids, fitting this requirement were found as promising INis . The present work reports the screening of 33 natural flavonoids (4 flavanones, 13 flavones, 15 flavonols and catechin), including many previously uninvestigated compounds, in fluorescence assays testing HIV-IN LTR vDNA binding and 3′ single strand processing catalytic inhibition. Selected hydroxy-, methoxy- and prenylsubstituted compounds and glycosides were investigated in order to gain deeper insight in the structural requirement of INis. For binding and 3′-processing assays, purified recombinant HIV-1 integrase and a 27 bp synthetic double stranded DNA with the viral 5′ LTR sequence were used. The compounds were tested at 100 µM concentration in comparative tests using positive controls unlabeled 5' LTR viral DNA for IN DNA binding, and L708-906 for catalytic 3′ processing inhibition assay.
It was found that flavonol-type compounds with 3′,4′-dihydroxy substitution, such as quercetin, physetin, and rhamnetin have the highest viral DNA binding inhibitory effect. Glycosylation at position 7 had no influence, but at position 3 reduced this activity. In case of flavonol 7-O-monoglycosides, moderate catalytic inhibition was also observed. The most interesting compounds were gossypitrin and herbacitrin with double inhibitory activity.
The present work was supported by PN-II-PT-PCCA-2013-4-0930, European cooperation ERA-NET HIVERA contract 11/2016 and NKFIH NN 118176.
 Maurin C, Bailly F, Cotelle P. Curr Med Chem 2003; 10: 1795-1810