Title:Small-molecule Inhibitors of HIV-1 Reverse Transcriptase-Associated Ribonuclease H Function: Challenges and Recent Developments
Volume: 28
Issue: 30
Author(s): Valentina Noemi Madia, Antonella Messore, Alessandro De Leo, Valeria Tudino, Ivano Pindinello, Francesco Saccoliti, Daniela De Vita, Luigi Scipione, Roberta Costi*Roberto Di Santo
Affiliation:
- Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur - Fondazione Cenci Bolognetti, “Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Rome,Italy
Keywords:
Ribonuclease H, reverse transcriptase, metalloenzyme, RNase H inhibitors, drug design, HIV-1, AIDS,
antiviral.
Abstract:
Multiple combinations of antiretroviral drugs have remarkably improved the
treatment of HIV-1 infection. However, life-long treatments and drug resistance are still an
open issue that requires continuous efforts for the identification of novel antiviral drugs.
Background: The reverse transcriptase-associated ribonuclease H (RNase H) hydrolyzes
the HIV genome to allow synthesizing viral DNA. Currently, no RNase H inhibitors
(RHIs) have reached the clinical phase. Therefore, RNase H can be defined as an attractive
target for drug design.
Objective: Despite the wealth of information available for RNase H domain, the development
of RHIs with high specificity and low cellular toxicity has been disappointing.
However, it is now becoming increasingly evident that reverse transcriptase is a highly
versatile enzyme, undergoing major structural alterations to complete its catalysis, and
that exists a close spatial and temporal interplay between reverse transcriptase polymerase
and RNase H domains. This review sums up the present challenges in targeting RNase H
encompassing the challenges in selectively inhibiting RNase H vs polymerase and/or
HIV-1 integrase and the weak antiviral activity of active site inhibitors, probably for a
substrate barrier that impedes small molecules to reach the targeted site. Moreover, the
focus is given on the most recent progress in the field of medicinal chemistry that has led
to the identification of several small molecules as RHIs in the last few years.
Conclusion: RHIs could be a new class of drugs with a novel mechanism of action highly
precious for the treatment of resistant HIV strains.
