Abstract
Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.
Highlights
As of 2017, 75% of FDA-approved antivirals target discrete stages of the virus replication cycle by inhibiting the activity of virus-encoded proteins [1]
Parallel studies revealed a similar pattern of altered HIV-1 protein expression in the context of the J-Lat 10.6 cell line, with a reduction of both Gag and GFP synthesis at low μM doses of GPS491
The ability of GPS491 to induce changes in HIV-1 RNA accumulation that correlate with inhibition of virus replication suggested that we examine whether GPS491 affected replication of adenovirus, another virus with a similar dependence on the host RNA
Summary
As of 2017, 75% of FDA-approved antivirals target discrete stages of the virus replication cycle (entry, genome replication, proteolytic cleavage of viral proteins) by inhibiting the activity of virus-encoded proteins [1]. Altering the ability of a virus to effectively use a host cell process may provide an alternative strategy to impede virus replication, generating a more robust barrier to virus resistance, and affect a broader spectrum of viruses with a single agent. Examples of such host-targeted therapeutic (HTT) strategies include the modulation of cell signaling, protein trafficking, lipid metabolism, epigenetic modifications, and RNA processing [2,3,4,5,6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
