Viruses are genetic parasites that use their hosts for replication. Not strictly defined as living organisms, they have exacted a tremendous toll on human wellbeing throughout the ages. Notorious examples include Smallpox, one of the deadliest diseases in human history that killed 200 million people in the 20th century alone; the Influenza virus, which according to the WHO, results in up to 500,000 annual deaths, and during the Spanish flu pandemic, killed 50-100 million people worldwide; HIV the etiological agent of AIDS with estimated deaths exceeding 30 million people since its emergence in the 1980s.
Importantly, viruses continue to emerge. In Africa, Marburg and Ebola viruses are particularly deadly, while the global COVID-19 pandemic is a reminder of humankind's precarious vulnerability.
ViroBlock will focus on such viral threats using its technology to provide rapid solutions to current threats, emerging variants, and new viruses.
Ion channels and their blockers
All cells are surrounded by membranes, whether from animals, plants, or bacteria. However, as impermeable barriers, membranes require transport systems, such as channels, to regulate salts' passage through them. Therefore, it is no surprise that all living organisms possess many channels that allow them to control their interior and surroundings' salinity and acidity.
Ion channels have always been excellent targets for pharmaceutical point intervention. For example, Calcium channel blockers (e.g., verapamil shown above) are routinely used to combat hypertension by decreasing blood pressure. Similarly, Sodium and Potassium channel blockers are often used to treat cardiac arrhythmia.
Similarly, tampering with these channels often leads to lethality, exemplified by channel blockers being some of the most toxic agents known to man. For example, the paralytic shellfish toxin Saxitoxin and pufferfish Tetrodotoxin are both potent Sodium channel blockers. On the other hand, Curare blocks the channel in our nervous system that responds to acetylcholine (nicotinic acetylcholine receptor).
Interestingly, even though viruses are not defined as living organisms, they too have been shown to contain channels. For example, ion channels are found in the viruses that cause the following diseases: Influenza, COVID-19, SARS, MERS, Hepatitis C, Dengue fever, West Nile fever, Zika fever, Ebola, Eastern equine encephalitis, and many more.
Importantly, blocking viral ion channels is a promising approach to curbing viral infectivity. In particular, amantadine (Symmetrel) and rimantadine (Flumadine) are anti-flu agents that work by blocking the virus' channel. Regrettably, resistance to both agents is currently widespread, limiting their use and meriting new blockers' search.
The threat from viral diseases fully embodies Bacon's assertion regarding the importance of a continuous search for new remedies:
``He that will not apply new remedies must expect new evils for time is the greatest innovator.''
Sir Francis Bacon, Of Innovations', Essays, 24 (1625)
One of the leading causes for this predicament is the notoriously low viral genetic information replication fidelity. For example, the error rates of HIV reverse transcriptase and influenza RNA polymerase are 10-3 and 10-4, respectively, compared to replication errors of mammalian genomes, which are six orders of magnitude lower. The poor accuracy of genomic replication leads to constant genetic drifts and shifts that change antigen epitopes and viral drug targets. In the former case, immunity is abolished, necessitating new vaccinations, while cognate antiviral agents may become ineffective in the latter.
Perhaps the biggest problem in combating the aforementioned evolutionary strategy of viruses is our inability to predict its specifics and plan for them ahead of time. We cannot design appropriate vaccines without specific knowledge of the new epitopes. Likewise, effective new antiviral drugs can not be created if the drug target keeps changing. Meanwhile, the medical community can only wait until a new viral isolate is identified that is refractive to current therapy. Only then can the resistant virus be examined and the exact resistance mechanism (i.e., mutations) identified. We realize that one can accelerate evolutionary processes in laboratory experiments with the hopes of developing resistance. However, such gain-of-function experiments are not without considerable medical risk or controversy if the mutated virus were to escape the laboratory confines.
To that end, ViroBlock developed an approach to map the pathogen's resistance options against its inhibitor before any clinical use. Utilizing this approach to Influenza, we rapidly identified all clinically known resistant mutations in a completely unbiased and risk-free manner.
Off-label use of approved medications (a.k.a. drug repurposing or repositioning) may be one of the fastest routes to abate any disease due to the shortening of regulatory steps. Notable success stories include aspirin to treat coronary-artery disease, sildenafil to combat erectile dysfunction, erythromycin for impaired gastric motility, and thalidomide to treat multiple myeloma.
However, the most important examples of repurposing that pertain to antiviral work are the discoveries of the first drugs against AIDS and COVID-19:
The repurposing of azidothymidine (AZT, shown above) to combat AIDS was reported more than twenty years after its first description in 1964. Similarly, Remdesivir, the first drug approved for use against COVID-19, was repurposed twice. It was initially developed to treat hepatitis C and respiratory syncytial virus and subsequently repurposed to treat infections caused by Ebola and Marburg viruses.
Additionally, repurposing can be a starting point for medicinal chemistry modification leading to more efficacious hits.
Look at the following article from the Drug Discovery World to get a broad perspective on drug repurposing.