Authors: Peter Barlow (Edinburgh Napier University, UK)
Take a look behind the scenes of a recent Future Virology review entitled ‘Antiviral therapeutic approaches for human rhinovirus infections’ as we ask author Peter Barlow (Edinburgh Napier University, UK) about antivirals, antibodies and the host response.
What inspired you to write this review?
Finding an effective and targeted treatment for rhinovirus is a challenge that has been the subject of extensive study over the past few decades. There have been many potential antiviral therapeutics investigated for their ability to inhibit the virus, but an effective treatment has remained elusive.
Given that our work, and the excellent work of others, has recently reinvigorated the interest in discovering a therapeutic approach for this virus, we felt it timely to reflect on the work that has already taken place in this area, particularly since many of the concepts are worth revisiting in the context of current work.
What are the key antiviral host defense peptides against human rhinoviruses?
We have investigated the activities of the human cathelicidin LL-37, the porcine cathelicidin Protegrin-1 and the ovine cathelicidin SMAP-29 and found them all to have varying, but effective, antiviral activity against rhinovirus. They key question now is whether derivatives, fragments or synthetic analogs of these peptides could be generated with greater efficacy against these viruses.
One of the biggest challenges in terms of finding a treatment for rhinovirus is the fact that there are so many strains circulating at any one time (almost 160 identified so far), it’s very difficult to find a drug that will effectively target all or most of the strains with a high efficacy. One strategy may therefore be to identify a therapeutic target that is common to all strains of the virus.
Amongst the current licensed antiviral drugs, which have the most promising activity against rhinoviruses? Could likely is it that these could be repurposed?
Two antiviral drugs, pleconaril and ribavarin have previously been shown to have activity against a number of different strains of rhinovirus, but not all of them. Pleconaril works by altering the binding of viral pathogens to host cell receptors and blocking uncoating. Ribavarin interferes with the synthesis of viral mRNA, and has been used for the treatment of hepatitis C virus and, in some instances, respiratory syncytial virus. I suspect that analogs of these drugs could have a broader spectrum of activity against other rhinovirus strains and should definitely be explored.
There are a number of other capsid-binding drugs that work in much the same way as pleconaril, as well as drugs that can block virus-encoded enzymes and host cell cholesterol trafficking, which may inhibit viral replication, and these are interesting prospect for further work.
Can we target components of our own host response as a therapeutic treatment strategy against rhinovirus?
A very recent study by a team led by Professor Ed Tate in Imperial College, London (UK), and published in Nature Chemistry, has identified an inhibitor of the human proteins NMT1 and NMT2, which are required for rhinovirus replication. This is a fantastic and novel strategy for targeting this virus and I’m excited to see where it leads.
Other studies have looked to inhibit host cell oxysterol binding protein (OSBP) and phosphatidylinositol 4-kinase III beta (PI4KB), which are also involved in viral replication, so these are also very promising approaches.
How promising are antibody therapies against rhinovirus?
Neutralizing antibodies have been investigated in the context of this virus, but again, we run up against the problem of strain diversity. Studies have used antibodies raised against the VP4 viral protein and I think these do represent a promising approach that would be valuable to take further. Alternatively, targeting of cellular ICAM-1 in mice does inhibit infection for major groups of the virus but the minor group viruses can use the LDL receptor on cells which is more problematic.
In summary, it’s encouraging that a new wave of antiviral molecules and approaches have been characterized over the past 2–3 years, and I’m excited to see more developments in this area.
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