Viruses cause serious disease and remain a global threat tohuman health. During infection, viruses hijack host cells and modify numerouscellular processes aiming to create a cellular environment favourable for virusreplication. Modification of cellular gene expression, cell cycle regulationand perturbation of cell signalling pathways are examples of cellular processesfrequently modified during virus infection.
The modulation of these pathwayscan disrupt normal cell physiology and often contributes to virus mediateddisease. In order to counteract these disease-causing viruses, anti-viral drugsare developed in an aim to disrupt the virus, with an ultimate goal oferadicating it from the human hostJW1 .While each virus utilises different machinery within thecell to cause infection, there are 6 fundamental steps which occur during theinfection cycle of host cells. The first involves the virion binding to a susceptiblehost cell, through receptors or other means. The next step involves entry intothe host cell through fusion with host cell membranes or transporter proteins.
This then leads to the release of the viral genome into the host cell. Thereplication of this genome then occurs. This leads to the synthesis of viralproteins and formation of a second generation of viron to form. These newlyformed virons are then released. The understanding of the specific cycle ofinfection and machinery utilised by a virus can be extremely useful in the developmentof drugs to disrupt this process.There is an ever-present need for the development of newanti-viral approaches. The main approaches to combat viral infections includethe development of vaccines and anti-viral drugs.
Whilst proven to beeffective, the development processes of these anti-viral approaches can beexpensive and time consuming due to the rigorous testing required to ensureeffectiveness and patient safety. Even after approval, there are many pitfallsof using of the approvedJW2 drug, one being drug resistance. A major cause of antiviral drug resistance ismutation within the viral genome. An aim for many virologists and pharmacologists is todevelop a drug which can effectively act on a range viruses.
Broad spectrumantivirals are available however due to the highly variable nature of viruses,drugs are usually specific to one virus or virus subset which share a unique drugtarget. There are two main types of anti-viral drugs: direct acting anti-virals(DAAs) (which bind to specific viral proteins) and host acting (which targetcellular processes within the host cell). The first anti-viral drug developedand approved by the FDA was idoxuridine in June 1963 and was used to treat herpessimplex keratitis(De Clercq and Li, 2016).Idoxuridine (5-iodo-2?-deoxyuridine) is an analogue of thymidine and isincorporated into viral DNA after phosphorylation by cellular kinases into itsactive 5′ – triphosphate form. Due to the halogen side group, when theactivated 5-iodo-2′-deoxyuridine is incorporated into DNA, it stops the bindingof base pairs and inhibits viral polymerase action.
This disrupts thereplication of Herpes simplex DNA and therefore its ability to replicate. Sincethis finding other effective anti-viral compounds have been developed. An observational study into of the time taken for anantiviral drug to be approved in the UK found that between 1981 and 2014 ittook an average of 77.2 months from the start of clinical development to approval (Ward et al., 2015).
This study did notconsider the time taken for the drug target to be established or preclinicalscreenings, suggesting the actual time to approval is lengthier. The evolutionof high throughput screening methods for preclinical trials has allowed thescreening of potential active chemicals on a target to be more efficient.Thousands of compounds can be screened per day and compounds which are activeon the target can then advance for further testing. Effectiveness and safety ina clinical setting during clinical trials however, remains the rate-limitingstep from lead compound to FDA approval as an anti-viral treatment. Due to thelength of time in development, if an outbreak does occur and an epidemicensues, as seen recently with the Ebola outbreak, and antiviral drugs andvaccines are not developed in enough time, this could prove to be catastrophicto the human population. Between 1963 and April 2016, 90 antiviral drugs wereapproved by the FDA to treat viral infections(De Clercq and Li, 2016).Antiviral drugs help to fight viruses which are either symptomatic and poseproblems to everyday life or could cause premature death if left untreated.
Oneof the most prevalent viruses around today is the human immunodeficiencyvirus-1 (HIV-1). As of 2016, 36.7 million people were living with HIV and thevirus is accountable for 35 million deaths since its occurrenceJW3 3. Withoutthe development of anti-retroviral drug therapies such as highly activeantiretroviral therapy (HAART), which target numerous stages of the viruslifecycle using a combination of different antiviral drugs, patients with theHIV infection would not be able to live as long or as healthily. A study whichshows this was released by the UK collaborative HIV cohort (UK CHIC) whichsuggested the life expectancy of people with HIV before and afterantiretroviral therapy (ART) increased to the same average life expectancy ofthe general population of the UK (May et al.
, 2014). Drug repurposing is a way of using approved or clinicallytested drugs for new conditions which they were not originally developed for.This has many advantages, including prior knowledge of safe dosage,pharmokinetics and pharmodynamics data and therefore allows specific testingcriteria of clinical trials to be bypassed, reducing the time and expense ofnew drug development. Although promising, drug repurposing also comes with manychallenges which shall be explored in this study. This study will review a sample of our current arsenal ofanti-viral compounds, review their mechanism of actions, cost and effectivenessand discuss the benefits and drawbacks of traditional drug developmentapproaches versus drug repurposing.