Classical drugs target the viral enzymes reverse transcripta

Classical drugs target the viral Pyrene azide 3 reverse transcriptase (RT), protease and integrase (IN) [[4], [5], [6]]. Raltegravir (ISENTRESS/MK-0518) is the prototypical integrase strand transfer inhibitor (INSTI) leading to an extremely strong reduction in viral load [7] and it has been approved for clinical use [8]. However, raltegravir resistance has been reported to be generated readily in the clinic [9] even in the presence of optimized HAART regimens [10]. There have been increasing demands on the development of the HIV-1 integrase (IN) inhibitor of the second generation. In particular, a developing strategy targeting the host factors involved in the interactions between HIV-1 IN and cellular cofactors has attracted increasing attention in the HIV drug discovery field [11]. We have previously reported that the 15, 18 and 21 nucleotide deletions in HBV preS1 start region in chronic patients with genotype C2 infection could contribute into disease progression via up-regulation of HBV replication [[12], [13], [14]]. Therefore, we hypothesized that overlapping polymerase region corresponding to preS1 deletions (5–7 amino acids) could be involved in the HBV replication, probably due to their antiviral responses. Here, we sought to evaluate the anti-HIV-1 activity of 3 types of HBV polymerase-derived peptides, designated Poly5, Poly6 and Poly7. In this course, we serendipitously found that a 6-mer peptide, Poly6 exerts a strong anti-HIV-1 activity, mainly via the inhibition of viral IN activity. We therefore explored the possible antiviral role of Poly6 against HIV-1, focusing on the mechanism regarding viral inhibition in the current study.
Materials and Methods
Results
Discussion To our surprise, we serendipitously discovered Poly6, an HBV polymerase-derived 6-mer peptide capable of exerting a potent anti-HIV-1 activity. It could provide a partial hint regarding why and how HBV variants with preS1 deletions that are reported to be related to the severity of liver disease, such as hepatocellular carcinoma, could increase their replication [[12], [13], [14]], possibly due to loss of antiviral peptide in an overlapping polymerase. This issue remains to be studied in the future. HIV-1 IN conducts the insertion of pro-viral DNA into the host cell genome, an essential step in its life cycle [6]. The IN interacts with a wide range of different host cellular cofactors throughout the viral life cycle. Inhibitors capable of disrupting interactions between IN and IN cellular cofactors would afford the development of a novel class of therapeutics to complement existing HIV-1 treatment regimens [25]. The p300, a cellular acetyltransferase that regulates chromatin conformation through the acetylation of histones, is one of IN interacting cellular cofactor, which can regulate viral IN by acetylation [26,27]. Our data showed that Poly6 exerts anti-HIV-1 activity via the inhibition of IN acetylation by suppressing p300 expression (Fig. 4B–C), suggesting that Poly6 may be a novel type of IN cellular cofactor inhibitor targeting p300. Issues regarding the mechanism of p300 down-regulation by Poly6, such as the involved cell signaling pathway or the regulation phase (transcriptionally or post-transcriptionally) are currently underway.
Author contributions
Conflicts of interest
Acknowledgements This work was supported by the National Research Foundation of Korea funded by the Ministry of Education (Grant No. NRF-2016R1A2B4011847).
Introduction Earlier research on the development of effective anti-HIV agents has focussed on inhibitors of the critical HIV-1 enzymes, reverse transcriptase (RT) and protease (PR) [1], [2]. The emerging challenges of drug resistance have been addressed using combinations of RT and PR inhibitors in what is known as ‘Highly Active Anti-Retroviral Therapy (HAART)’ – an approach which has enjoyed considerable success [3]. Nevertheless, there is an urgent need to develop new and more effective therapeutics and the drug targets have been extended to include HIV-1 integrase (IN) inhibitors [4], which either block the strand transfer of viral DNA into the host genome or disrupt the 3′-processing of the viral DNA LTR units [5]. Since the approval of raltegravir 1 [6] for clinical use by the FDA in 2007, other potential scaffolds have been explored, inter alia the β-diketo acid (DKA) moiety [7], which is present in compound 2 [8] and which is capable of coordinating metal ions in the enzyme active site.