Biological Evaluation of Molecules of the azaBINOL Class as Antiviral Agents: Specific Inhibition of HIV-1 RNase H Activity by 7-Isopropoxy-8-(naphth-1-yl)quinoline

Ross D. Overacker; Somdev Banerjee; George F. Neuhaus; Selena Milicevic Sephton; Alexander Herrmann; James A. Strother; Ruth Brack-Werner; Paul R. Blakemore; Sandra Loesgen

RNase H inhibition of HIV-1 RT is an under explored and under-utilized mechanism of 273 inhibition. The azaBINOL compounds reported here represent novel scaffolds that inhibit HIV 274 via an underexplored allosteric mechanism with low toxicity and high specificity. In particular, 275 the isopropyl ether derivative of 2´-deoxy-8-azaBINOL (B#24) exhibits with potent and specific 276 antiviral activity against HIV RNase H. We utilized time-of-addition experiments and 277 recombinant enzyme assays to show that B#24 specifically inhibits RNase H. In addition, we 278 used BLI to show that B#24 binds to HIV RT via a 1:1 binding mechanism with a binding 279 affinity (KD) of 38 µM. Although a number of azaBINOL compounds within the screened library 280 were found to have limited solubility in the cell-based assays as expected, aggregation and non-281 specific inhibition was tested thoroughly and can be dismissed for lead compound B#24 (SI Fig 282 6 ,7). 283 All rights reserved. No reuse allowed without permission.