Introduction

There are at present some 40 antiviral drugs that have been

formally licensed for clinical use in the treatment of viral
infections (Table 1).1 These are mainly used in the treatment of
infections caused by human immunodeficiency virus (HIV),
hepatitis B virus (HBV), herpes viruses (herpes simplex virus
(HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV)),
orthomyxoviruses (influenza), paramyxoviruses (respiratory
syncytial virus (RSV)), and hepaciviruses (hepatitis C virus (HCV)).
As these are the viruses that are most in demand of antiviral
therapy, they have prompted the search for new antiviral
strategies and drugs directed toward either the same molecular
targets as the approved antiviral drugs or to other targets.

Most of the newly

described antiviral
compounds (that are currently
in development) are targeted
at HIV, HBV, or HCV. Some are
targeted at HSV, VZV, or CMV,
but, there are in addition many
other important viral
pathogens for which medical
intervention, either
prophylactic or therapeutic, is urgently needed, and, these are,
among the DNA viruses, the papillomaviruses (human papilloma
virus
(HPV)), adenoviruses, poxviruses (variola, vaccinia, monkeypox,
etc.) and the herpesviruses Epstein–Barr (EBV) and human
herpesvirus type 6 (HHV-6), and, among the RNA
viruses, enteroviruses (e.g., Coxsackie B and
Echo), coronaviruses (e.g., severe acute respiratory
syndrome (SARS)-associated
coronavirus), flaviviruses (e.g., dengue, yellow fever), and other
RNA viruses associated with hemorrhagic fever (arenaviruses
(e.g., Lassa fever), bunyaviruses (e.g., Rift Valley fever, Crimean–
Congo fever), and filoviruses (e.g., Ebola and Marburg)).

Main AntiViral Drug Families

Cidofovir

Cidofovir is an injectable antiviral medication

employed in the treatment of cytomegalovirus
(CMV) retinitis in patients diagnosed with AIDS.
It suppresses CMV replication through selective
inhibition of viral DNA synthesis. It was
manufactured by Gilead and initially approved
by the FDA in 1996, but has since been
discontinued.

Aciclovir
Aciclovir is active against Herpes simplex virus type 1 (HSV-1),
HSV-2, Varicella zoster virus (VZV), Herpesvirus simiae, and to a
lesser degree Epstein-Barr virus (EBV). Resistant strains of HSV
can arise owing to the emergence of thymidine kinase-deficient
mutants. Other forms of resistance patterns are less common
[2,3].

Aciclovir is used topically or

systemically, orally or intravenously. Its
therapeutic potential is most impressive
in active parenchymal or systemic HSV
infections. The latency stage of the viral infection is not affected.
Since the blood–brain barrier is well penetrated, aciclovir is the
treatment of choice for HSV encephalitis.

Amantadine
An antiviral that is used in the prophylactic or symptomatic
treatment of influenza A. It is also used as an
antiparkinsonian agent, to treat extrapyramidal
reactions, and for postherpetic neuralgia. The
mechanisms of its effects in movement disorders
are not well understood but probably reflect an
increase in synthesis and release of dopamine,
with perhaps some inhibition of dopamine uptake.

Abacavir

Abacavir (ABC) is a powerful nucleoside

analog reverse transcriptase inhibitor
(NRTI) used to treat HIV and AIDS.
Chemically, it is a synthetic carbocyclic
nucleoside and is the enantiomer with 1S,
4R absolute configuration on the
cyclopentene ring. In vivo, abacavir
sulfate dissociates to its free base,
abacavir.

Amprenavir
is a protease inhibitor used to treat HIV infection. It was approved
by the Food and Drug Administration on April 15, 1999, for twice-
a-day dosing instead of needing to be taken every eight hours.
The convenient dosing came at a price, as the dose required is
1,200 mg, delivered in 8 (eight) very large 150 mg gel capsules or
24 (twenty-four) 50 mg gel capsules twice daily.

Boceprevir
Boceprevir is a direct acting
antiviral medication used as part
of combination therapy to treat
chronic Hepatitis C, an infectious
liver disease caused by infection
with Hepatitis C Virus (HCV). HCV
is a single-stranded RNA virus
that is categorized into nine
distinct genotypes, with
genotype 1 being the most
common in the United States, and
affecting 72% of all chronic HCV patients .

Fomivirsen

Fomivirsen is a antisense 21 mer phosphorothioate

oligonucleotide. It is an antiviral agent that was used in the
treatment of cytomegalovirus retinitis (CMV) in
immunocompromised patients, including those with AIDS. As a
complementary nucleotide to the messenger RNA of the major
immediate-early region proteins of human cytomegalovirus, it
disrupts the replication of the virus through an antisense
mechanism

Famciclovir
Famciclovir, marketed as Famvir
by Novartis, is a guanine
analogue used to treat herpes
virus infections. It is most
commonly used to treat herpes
zoster (shingles). Famciclovir is a
prodrug of penciclovir with higher
oral bioavailability.

Ganciclovir
An acyclovir analog that is a
potent inhibitor of the Herpesvirus
family including cytomegalovirus.
Ganciclovir is used to treat
complications from AIDS-associated
cytomegalovirus infections.

Imiquimod

Imiquimod is an immune response modifier that acts as a toll-like

receptor 7 agonist. Imiquimod is commonly used topically to treat
warts on the skin of the genital and
anal areas. Imiquimod does not cure
warts, and new warts may appear
during treatment. Imiquimod does not
fight the viruses that cause warts
directly, however, it does help to
relieve and control wart production.
Miquimod is also used to treat a skin
condition of the face and scalp called
actinic keratoses and certain types of skin cancer called
superficial basal cell carcinoma

Oseltamivir
Oseltamivir, is an antiviral neuraminidase inhibitor used for the
treatment and prophylaxis of infection with
influenza viruses A (including pandemic
H1N1) and B. Oseltamivir exerts its antiviral
activity by inhibiting the activity of the viral
neuraminidase enzyme found on the surface
of the virus, which prevents, viral replication,
and infectivity.

Rimantadine

An RNA synthesis inhibitor that is

used as an antiviral agent in the
prophylaxis and treatment of
influenza.

Telbivudine

Telbivudine is a synthetic thymidine nucleoside

analog with specific activity against the hepatitis
B virus. Telbivudine is orally administered, with
good tolerance, lack of toxicity and no dose-
limiting side effects.

Baloxavir marboxil

Baloxavir marboxil is an antiviral

drug developed by Shionogi Co., a Japanese pharmaceutical
company and Roche for the treatment of influenza A and influenza
B infections. The drug was initially approved for use in Japan in
February 2018 and approved by the FDA on October 24, 2018 ,for
the treatment of acute uncomplicated influenza in patients 12
years of age and older who have been symptomatic for no more
than 48 hours . Baloxavir marboxil, a cap-endonuclease inhibitor,
has a unique mechanism of action when compared to the
currently existing neuraminidase inhibitor drug class used to treat
influenza infections .

Atazanavir

Atazanavir (formerly known as BMS-232632) is an antiretroviral

drug of the protease inhibitor (PI) class. Like other antiretrovirals,
it is used to treat infection of human immunodeficiency virus
(HIV). Atazanavir is distinguished from
other PIs in that it can be given once-daily
(rather than requiring multiple doses per
day) and has lesser effects on the
patient's lipid profile (the amounts of
cholesterol and other fatty substances in
the blood). Like other protease inhibitors,
it is used only in combination with other
HIV medications. The U.S. Food and Drug
Administration (FDA) approved atazanavir
on June 20, 2003.

Daclatasvir
Daclatasvir is a direct-acting antiviral
agent against Hepatitis C Virus (HCV)
used for the treatment of chronic HCV genotype 1 and 3 infection.
It is marketed under the name DAKLINZA and is contained in daily
oral tablets as the hydrochloride salt form . Hepatitis C is an
infectious liver disease caused by infection with Hepatitis C Virus
(HCV). HCV is a single-stranded RNA virus that is categorized into
nine distinct genotypes, with genotype 1 being the most common
in the United States, and affecting 72% of all chronic HCV
patients . Daclatasvir was the first drug with demonstrated safety
and therapeutic efficacy in treating HCV genotype 3 without the
need for co-administration of interferon or Ribavirin. It exerts its
antiviral action by preventing RNA replication and virion assembly
via binding to NS5A, a nonstructural phosphoprotein encoded by
HCV. Binding to the N-terminus of the D1 domain of NS5A
prevents its interaction with host cell proteins and membranes
required for virion replication complex assembly. Daclatasvir is
shown to target both the cis- and trans-acting functions of NS5A
and disrupts the function of new HCV replication complexes by
modulating the NS5A phosphorylation status . The most common
critical NS5A amino acid substitutions that led to reduced
susceptibility to daclatasvir therapy occured at position Q30
(Q30H/K/R) and M28 in genotype 1a patients and Y93H in
genotype 3 patients.

Docosanol

Docosanol is a drug used for topical

treatment for recurrent herpes simplex
labialis episodes (episodes of cold
sores or fever blisters). A saturated 22-
carbon aliphatic alcohol, docosanol
exhibits antiviral activity against many
lipid enveloped viruses including
herpes simplex virus (HSV). Docosanol
inhibits fusion between the plasma membrane and the herpes
simplex virus (HSV) envelope, thereby preventing viral entry into
cells and subsequent viral replication.

Conclusion
About 40 compounds are registered as antiviral drugs, at least
half of which are used to treat HIV infections. An even greater
number of compounds are under clinical or preclinical
development, with again, as many targeting HIV as all the other
viruses taken together. This implies that HIV, since its advent, has
remained the main target in antiviral drug development. Antiviral
agents can, as guided by the anti-HIV agents as examples, be
divided in roughly five categories:

1- nucleoside analogs

2- nucleotide analogs (or acyclic nucleoside phosphonates)

3- nonnucleoside analogs

4- protease inhibitors, and 5- virus–cell fusion inhibitors.

Molecular targets are for (1) and (2) the viral DNA
polymerase (whether DNA-dependent as in the case
of herpesviruses, or RNA-dependent as in the case of HIV or HBV);
for (3) RNA-dependent DNA polymerase (reverse transcriptase),
associated with HIV, or RNA-dependent RNA polymerase (RNA
replicase) associated with HCV; for (4) the proteases associated
with HIV and HCV; and for (5) the fusion process of HIV (and,
potentially, other viruses such as the SARS coronavirus and RSV).
Antiviral agents may also exert their antiviral effects through an
interaction with cellular targets such as IMP
dehydrogenase (ribavirin) and SAH hydrolase (3-deazaneplanocin
A). The latter enzymes are essential for viral RNA synthesis
(through the supply of GTP) and viral mRNA maturation (through
5'-capping), respectively. Finally, interferons (now generally
provided in their pegylated form) may be advocated in the
therapy of those viral infections (actually, HBV and HCV;
prospectively, Coxsackie B, SARS,..) that, as yet, cannot be
sufficiently curbed by other therapeutic measures.

References