Viruses cause serious disease and remain a global threat to
human health. During infection, viruses hijack host cells and modify numerous
cellular processes aiming to create a cellular environment favourable for virus
replication. Modification of cellular gene expression, cell cycle regulation
and perturbation of cell signalling pathways are examples of cellular processes
frequently modified during virus infection. The modulation of these pathways
can disrupt normal cell physiology and often contributes to virus mediated
disease. In order to counteract these disease-causing viruses, anti-viral drugs
are developed in an aim to disrupt the virus, with an ultimate goal of
eradicating it from the human hostJW1 .
While each virus utilises different machinery within the
cell to cause infection, there are 6 fundamental steps which occur during the
infection cycle of host cells. The first involves the virion binding to a susceptible
host cell, through receptors or other means. The next step involves entry into
the 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. The
replication of this genome then occurs. This leads to the synthesis of viral
proteins and formation of a second generation of viron to form. These newly
formed virons are then released. The understanding of the specific cycle of
infection and machinery utilised by a virus can be extremely useful in the development
of drugs to disrupt this process.
There is an ever-present need for the development of new
anti-viral approaches. The main approaches to combat viral infections include
the development of vaccines and anti-viral drugs. Whilst proven to be
effective, the development processes of these anti-viral approaches can be
expensive and time consuming due to the rigorous testing required to ensure
effectiveness and patient safety. Even after approval, there are many pitfalls
of using of the approvedJW2
drug, one being drug resistance. A major cause of antiviral drug resistance is
mutation within the viral genome.
An aim for many virologists and pharmacologists is to
develop a drug which can effectively act on a range viruses. Broad spectrum
antivirals 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 drug
target. There are two main types of anti-viral drugs: direct acting anti-virals
(DAAs) (which bind to specific viral proteins) and host acting (which target
cellular processes within the host cell). The first anti-viral drug developed
and approved by the FDA was idoxuridine in June 1963 and was used to treat herpes
simplex keratitis(De Clercq and Li, 2016).
Idoxuridine (5-iodo-2?-deoxyuridine) is an analogue of thymidine and is
incorporated into viral DNA after phosphorylation by cellular kinases into its
active 5′ – triphosphate form. Due to the halogen side group, when the
activated 5-iodo-2′-deoxyuridine is incorporated into DNA, it stops the binding
of base pairs and inhibits viral polymerase action. This disrupts the
replication of Herpes simplex DNA and therefore its ability to replicate. Since
this finding other effective anti-viral compounds have been developed.
An observational study into of the time taken for an
antiviral drug to be approved in the UK found that between 1981 and 2014 it
took an average of 77.2 months from the start of clinical development to approval (Ward et al., 2015). This study did not
consider the time taken for the drug target to be established or preclinical
screenings, suggesting the actual time to approval is lengthier. The evolution
of high throughput screening methods for preclinical trials has allowed the
screening of potential active chemicals on a target to be more efficient.
Thousands of compounds can be screened per day and compounds which are active
on the target can then advance for further testing. Effectiveness and safety in
a clinical setting during clinical trials however, remains the rate-limiting
step from lead compound to FDA approval as an anti-viral treatment. Due to the
length of time in development, if an outbreak does occur and an epidemic
ensues, as seen recently with the Ebola outbreak, and antiviral drugs and
vaccines are not developed in enough time, this could prove to be catastrophic
to the human population.
Between 1963 and April 2016, 90 antiviral drugs were
approved by the FDA to treat viral infections(De Clercq and Li, 2016).
Antiviral drugs help to fight viruses which are either symptomatic and pose
problems to everyday life or could cause premature death if left untreated. One
of the most prevalent viruses around today is the human immunodeficiency
virus-1 (HIV-1). As of 2016, 36.7 million people were living with HIV and the
virus is accountable for 35 million deaths since its occurrenceJW3
the development of anti-retroviral drug therapies such as highly active
antiretroviral therapy (HAART), which target numerous stages of the virus
lifecycle using a combination of different antiviral drugs, patients with the
HIV infection would not be able to live as long or as healthily. A study which
shows this was released by the UK collaborative HIV cohort (UK CHIC) which
suggested the life expectancy of people with HIV before and after
antiretroviral therapy (ART) increased to the same average life expectancy of
the general population of the UK (May et al., 2014).
Drug repurposing is a way of using approved or clinically
tested 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 testing
criteria of clinical trials to be bypassed, reducing the time and expense of
new drug development. Although promising, drug repurposing also comes with many
challenges which shall be explored in this study.
This study will review a sample of our current arsenal of
anti-viral compounds, review their mechanism of actions, cost and effectiveness
and discuss the benefits and drawbacks of traditional drug development
approaches versus drug repurposing.