4e1m

Publication Abstract from PubMed

tert-Butoxy-(4-phenyl-quinolin-3-yl)-acetic acids (tBPQA) are a new class of HIV-1 integrase (IN) inhibitors that are structurally distinct from IN strand transfer inhibitors but analogous to LEDGINs. LEDGINs are a class of potent antiviral compounds that interacts with the LEDGF binding pocket on IN and were identified through competition binding against LEDGF. LEDGF tethers IN to the host chromatin and enables targeted integration of viral DNA. The prevailing understanding of the antiviral mechanism of LEDGINs is that they inhibit LEDGF binding to IN which prevents targeted integration of HIV-1. We show that in addition to the properties already known for LEDGINs, the binding of tBPQAs to the IN dimer interface inhibits IN enzymatic activity in a LEDGF-independent manner. Using the analysis of two long terminal repeat (2-LTR) junctions in HIV-infected cells, we showed that the inhibition by tBPQAs occurs at or prior to the viral DNA 3'-processing step. Biochemical studies revealed that this inhibition operates by compound induced conformational changes in IN dimer that prevent proper assembly of IN onto viral DNA. For the first time, tBPQAs are demonstrated to be allosteric inhibitors of HIV-1 IN displaying a dual mode of action: inhibition of IN/viral DNA assembly and inhibition of IN/LEDGF interaction.

New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action.,Tsiang M, Jones GS, Niedziela-Majka A, Kan E, Lansdon EB, Huang W, Hung M, Samuel D, Novikov N, Xu Y, Mitchell M, Guo H, Babaoglu K, Liu X, Geleziunas R, Sakowicz R J Biol Chem. 2012 Apr 25. PMID:22535962^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.