Therapeutic Potential of Peptide Motifs Against HIV-1 Reverse Transcriptase and Integrase

Abstract

Multiple clinical benefits have been obtained thanks to the combination of drugs targeting several steps of the HIV-1 replication. However, despite such combination therapy, complete eradication of the virus cannot be attained. Moreover, emergence of resistance observed under treatment and the lengthening life expectancy of treated patients highlight the need for new anti-HIV agents. Peptide-based compounds that exhibit anti RT and anti integrase activities were particularly described. Active peptides have been obtained from several ongoing approaches. The study of interaction between viral proteins inside the preintegration complex, and the growing knowledge of interactions between viral proteins and cellular partners, have generated a useful source of data for the development of peptide inhibitors. Recent data were also obtained from the observation that viral enzymes such as RT and integrase are fully active when they are in a dimeric (RT) or oligomeric state. Peptides derived from the interface of dimers are also of interest. The obtention of efficient small molecules as competitive oligomerization inhibitors is problematic, but anyway, improved cellular uptake and chemical modifications that were obtained in the past ten years allowed numerous peptide drugs to reach the clinic. Finally, a new promising class of peptide inhibitors is emerging called "shiftides", which interfere with the ability of IN to adopt an oligomeric active state.

Resistance to Integrase Inhibitors

“…Clinical trials with S-1360 and L-870,810 were terminated in phase I/II and II due to limited efficacy and toxicity, respectively [34,35]. Peptides and nucleic acid inhibitors of IN in vitro have also been identified by screening (phage display, yeast 2-hybrids, SELEX) or rational design (derived from viral or cellular co-factors) [39,40]. Zintevir (AR177) (Aronex Pharmaceuticals) is a G-quadraduplex-forming oligonucleotide inhibitor of both recombinant IN and HIV-1 replication at low nanomolar concentration [41,42].…”

The Cellular Antiviral Protein APOBEC3G Interacts with HIV-1 Reverse Transcriptase and Inhibits Its Function during Viral Replication

“…In infected cells, RT employs tRNA 3 Lys and the polypurine tract as primers and converts the viral genomic RNA into doublestranded viral DNA (23). This process is catalyzed by both the DNA polymerase and RNase H activities of RT (23,49).…”

“…A number of studies have elucidated the mechanisms underlying the inhibition effect of A3G on reverse transcription. It has been shown that A3G is able to interfere with multiple steps of reverse transcription, including the inhibition of tRNA 3 Lys primer annealing through an interaction with NCp7 (18)(19)(20), the blocking of strand transfers, which consequently reduces late viral DNA synthesis (34,40), and the suppression of tRNA 3 Lys cleavage and removal, which produces aberrant viral 3= long terminal repeat (LTR) ends (40). Moreover, using purified catalytically active A3G protein, it was shown that all reverse transcriptase (RT)-catalyzed DNA elongation reactions were significantly inhibited by A3G (26).…”

Dimeric Switch of Hakai-truncated Monomers during Substrate Recognition

“…The findings from this study suggest that the dimeric architecture of the HYB domain is necessary to engage the Tyr(P) ligand, which is in sharp contrast to all the other known Tyr(P)-binding domains that predominantly function as monomers. Selectively targeting the dimeric interface of therapeutically important enzymes has emerged as an attractive method of allosteric inhibition (62)(63)(64)(65). The importance of the dimeric architecture of HYB in Tyr(P) substrate binding demonstrated by the present study makes it an ideal target for the design of selective allosteric inhibitors that abrogate HYB dimerization and potentially act as novel therapeutic interventions against cancer.…”