A time-lapse sequence of confocal fluorescence images of giant vesicles consisting of model viral envelope composition (an equimolar mixture of a phospholipid, sphingolipid, and cholesterol) upon incubation with 5 μM viral-encoded AH peptide. The peptide-binding-induced appearance of cholesterol-enriched domains highlights the importance of membrane composition and might suggest how the AH domain might, on the one hand, segregate molecules needed for viral assembly and, on the other, present peptides exhibiting broad-spectrum virocidal activity [Hanson and Gettel et al./Biophysical Journal 2016]
The rapid acquisition of drug resistance by viruses is a constant threat and an imminent concern of researchers across the globe. Scientists are always on the hunt to develop therapies that affect a broad range of viral invaders, as well as uncover the molecular mechanisms that lead their demise—all while reducing the possibility of developing resistance.
Now, a team of researchers from the University of California, Davis and Nanyang Technological University (NTU), Singapore have published data from a study that shows how a peptide derived from the hepatitis C virus (HCV) kills a broad range of viruses while leaving host cells unharmed. The investigators believe that peptide can discriminate between the molecular make-up of viral and host membranes.
“Although there are many antiviral drugs on the market, the common problem is that the virus learns how to evade them, becoming resistant to the drug treatment. There is a growing recognition that new classes of antiviral drugs that target multiple viruses are needed,” explained senior study author Atul Parikh, Ph.D., professor in the departments of biomedical engineering and chemical engineering and material science at UC-Davis. “Because the HCV-derived peptide appears to meet this need, we reason it targets the Achilles' heel of viruses—a lipid coating or membrane envelope less likely to become resistant to drugs targeting them.”
Previous work has shown that the peptide, known as HCV α-helical (AH) peptide, has broad antiviral properties— the same property that allows the peptide to hijack host cell structures for HCV replication also produces ruptures in viral membranes. However, the mechanism of why AH selectively attacks the viral envelope but not host cell membranes has eluded scientists and limited the peptide’s use in drug development.
To address this conundrum, the research team tested the AH peptide on simplified model lipid membranes that varied in their size and chemical composition. Upon exposure to the peptide, virus-like models with cholesterol-rich membranes showed molecular changes and an increase in openings, while not affecting cholesterol-free vesicles.
The findings from this study were published recently in Biophysical Journal through an article entitled “Cholesterol-Enriched Domain Formation Induced by Viral-Encoded, Membrane-Active Amphipathic Peptide.”
“These results are important not only for furthering the membrane-targeting strategy for developing antivirals against HCV using viral peptides but also for identifying other viruses, whose membrane compositions include comparable concentrations of cholesterol, that can be inhibited by the HCV antiviral,” noted co-author Nam-Joon Cho, Ph.D., associate professor at NTU. “Although several compounds that destabilize the viral membrane have been recently proposed, no drug on the market currently targets the lipid membrane.”
The researchers were excited by their findings and hope they will translate into therapeutic strategies for humans, but caution against over interpretation as more work is needed on model systems that more closely recapitulate viral and host cell membranes.
“These simplified model membranes are excellent models to dissect how drugs target lipid components of viral or cell membranes, but we need to remember that they are still models” Dr. Cho stated. “It will be important to extend the cues drawn from these studies to biological systems, namely human cells and live viruses, to validate the biophysical insights before preclinical translation can occur.”
The scientists are looking to continue their work into the effects of AH on other viral membranes, as well as establish collaborations with virologists to begin to explore translational opportunities.
“Understanding how the drug candidate interacts with these biologically important lipids, we reason, should open the door to deciphering the rich and complex biology of these systems and lead to new opportunities for antiviral strategies,” Dr. Parikh concluded. “Studies such as ours provide hope that replacing the old paradigm of 'one-bug, one-drug' with broadly applicable drugs against which viruses cannot develop resistance may become a reality soon.”