A broad-spectrum antiviral drug…finally!
Recent study has developed a new potential broad-spectrum drug for treating infections from Herpes Simplex Virus-1 and possibly other viruses in both new patients and who have got drug resistance from available drugs
The traditional therapeutic approach in medicine has always followed the ‘one-bug-one-drug’ paradigm, also sometimes called as ‘many for one’ in which a drug (or drugs) targets only one particular disease-causing organism in the body. Scientists and researchers worldwide are now moving away from this paradigm and adopting the alternative ‘one for many’ approach, specially in the case of antibiotics and also now antivirals. Broad-spectrum medicines are being developed which generally target multiple or all disease-causing organisms. For example, many broad-spectrum antibiotics are available today which act against a wide range of disease-causing bacteria (anti-bacterial antibiotics) and fungi (anti-fungal antibiotics). Such broad-spectrum antibiotics are very powerful and flexible drugs that can not only be used against wide variety of bacteria but can also be used to treat bacterial infections for which the causing bacteria is not known or identified yet. The most common, popular broad-spectrum antibiotic is the Ampicillin which can attack a variety of bacterial strains.
Similar to such antibiotics, broad-spectrum antiviral drugs will have a strategy to target different types of viruses. In adopting this approach for antivirals, researchers need to first identify the various characteristics of the host that viruses ‘depend on’ for their lifecycle. It is here that viruses are profoundly different from bacteria and since viruses hijack our (we are the host) cellular machinery, it is obviously much difficult to disrupt viral growth without causing disruption in a human cell function. But since a variety of viruses take advantage of the ‘same host function’, an antiviral drug can basically deprive the virus from any access to the host function. The underlying idea is to ‘stop’ one happening in the host which is enabling the virus to grow. This said, it should then be possible to design a broad-spectrum antiviral drug which ‘deprives’ and thus kills the virus, no matter which virus it is. Many narrow-spectrum antivirals have failed over the years because viruses are so different from bacteria, they also mutate much faster and any narrow-spectrum antiviral drug which is developed after years of labour generally has a very limited shelf life and anyway such antivirals have a very narrow scope of attack to begin with because they attack only a particular virus. As of 2018, we still don’t have any medication for so many nasty viruses, e.g. Ebola. Thus, we really need a strong, safe, viable wide-spectrum antiviral which can target only a host mechanism and thus will be able to deprive and kill a variety of viruses. In a recent breakthrough study, researchers have identified a mechanism in the host which if targeted can result in deprivation and killing of herpes simplex virus 1 and this same broad-spectrum therapeutic could be potentially applied to other viruses as well.
An estimated two-thirds of the world’s population who is under 50 years of age is infected by herpes simplex virus type 1 (HSV-1), which makes it to be more than 3.7 billion people worldwide, according to World Health Organization (WHO). Thus, HSV-1 is a very common contagious viral infection which is endemic throughout the world. The HSV-1 infection persists for a lifetime even if it is acquired during childhood or adolescence. This virus infects primarily the mouth and eyes but sometimes also genitalia. Like most viral infections, it spreads very easily and it is extremely challenging to prevent it. The handful of treatment drugs available for these infections are successful to a large extent, however the virus has emerged with drug-resistant strains especially after long-term use because most of these drugs follow a similar therapy approach. Thus, there is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV.
New therapy for HSV-1 infection
Infection in the eye can be temporarily eliminated using available antiviral drugs but inflammation in the cornea – outer layer of the eye ball – is seen to persist indefinitely leading to other conditions like glaucoma and blindness by overuse of steroids medication. The current drugs in the market, called nucleoside analogues, basically prevent the virus from producing a protein which is crucial for virus’s replication and growth. However, drug resistance is an important aspect and patients who develop resistance to these analogues are left with very limited options to treat HSV-1 infection. In a major recent study, published in Science Translational Medicine, researchers have identified a small drug molecule which clears the HSV-1 infection in the cells of the cornea and works very differently than the drugs that are available making it a promising alternative potential drug against HSV-1.
The authors have reported that this small drug molecule – called BX795 – clears the infection in human corneal cells (cultured in the laboratory) and also corneas of infected mice. This drug molecule follows a very novel way in which it acts on the host cells (instead of the infection, which is generally what the current drugs do) to clear up the viral infection. This molecule is an already known inhibitor of an enzyme TBK1 which is involved in immunity in the host, or more specifically in innate immunity and neuroinflammation. Innate immunity or our ‘in-born immunity system’ comprises of cells and mechanisms that defend us from infection by other organisms. Also, it has been established before that partial TBK1 deficiency results in neuroinflammatory or neurodegenerative disorders. In this study, when this enzyme gets suppressed (by adding TBK1), the viral infection was seen to be growing. However, quite unexpectedly and on the contrary, higher concentrations of BX795 was on the other hand clearing up the HSV-1 infection in cells. Though overall, lower concentrations of this molecule were required to clear the infection when compared to current drugs nucleoside analogues. No toxicity or any other effects were visible in the uninfected cells at these therapeutic concentrations. The authors do state here that a topical version of the dosage was used in the studies, though they are also in the midst of formulating a similar oral dosage.
Can BX795 be used to target other viral infections?
As this particular study this molecule only worked on the cells that were infected with HSV-1. The obvious question to ponder upon is whether a similar therapeutic approach can be applied to other critical viral infections like HSV-2 (herpes simplex virus 2) or even HIV (human immunodeficiency virus). The authors point out that since most viruses follow a common pathway to replicate inside a host cell, and BX795 targets that pathway, this can definitely be a new kind of broad-spectrum antiviral which could be used to treat other viral infections as well and could fill the gap that exists in the field of broad-spectrum antiviral drugs. For example, the novel mechanism of this drug where it targets the host cells should work on inhibiting HIV infections. And, Human Papillomavirus (HPV) infections could be possibly targeted in a similar way by blocking a process called AKT phosphorylation in the host cells which is essential for HPV to propagate. The authors are looking at having human clinical trials soon for this new drug molecule and since it has shown low toxicity, it can be a great potential for systemic use and also topical application.
However, the broad-spectrum aspect of these antivirals needs to be taken with caution since it is widely reported that they might cause other problems in the body, like risk of immune system deregulation and also enhanced toxicity in the cells. The proper dosage of such a drug also needs to be decided with care. Further, translating the laboratory studies successfully to testing in animals (e.g. mice) is also crucial. Sometimes our immune system will attack antiviral drugs assuming that drug to be an invader instead, because the antiviral is technically aiming to ‘target’ a host mechanism. Also, the whole process of ‘laboratory to animal testing to human testing’ is loaded with potential failures for such antivirals because sometimes drugs that work in mice are totally useless in humans. Our body is filled with beneficial viruses too (trillions maybe) which may actually be essential to our health, including some microbe-infecting viruses and a wide-spectrum antiviral might deprive these good viruses too and killing them which is not an ideal scenario that we desire. It is no doubt that alternative broad-spectrum antivirals are definitely required as drug resistance is becoming a global problem and we don’t even have drugs for so many viruses. This discovery looks promising for new patients as well as for patients who have developed resistance against the available drugs. Also, such an antiviral drug could be used to target multiple viruses, which can lead to breakthroughs. Further steps are to be taken in the direction of establishing the accurate potential of this new drug molecule and the authors hope for a topical version of this drug within the next three years.
Jaishankar et al., 2018, ‘An off-target effect of BX795 blocks herpes simplex virus type 1 infection of the eye’, Science Translational Medicine, vol. 10, no. 428, eaan5861, DOI: 10.1126/scitranslmed.aan5861