Antiviral Chemotherapy

Department of Pharmaceutical Microbiology,
Faculty of Pharmacy, University of Benin, Benin City.

Dr. Godfrey E. Umhenin
(B.Pharm, PharmD, M.Sc, MPSN)
godfrey.umhenin@uniben.edu
COURSE CODE: PMB 513
ANTIVIRAL CHEMOTHERAPY
Learning objectives:
At the end of this module, students should be aware of:
 Targets for antiviral agents
 Various stages of HIV infection
 The life cycle of HIV and target for various classes of antiretroviral agents
 Goals and principles of antiretroviral therapy
 Classes of antiviral agents
Introduction
Viruses are obligate intracellular parasites. They cannot survive outside their host. They
have no metabolic machinery of their own. Instead, they rely o n the metabolic
machinery of their host. The multiple stages of viral replication suggests the possibility
for the development of different classes of antiviral agents that can act on each stage of
viral replication. Effective antiviral agents must specifically inhibit viral specific
replicating events or preferentially inhibit viral directed rather than host cell directed
nucleic acid/protein synthesis.
Targets for antiviral agents

In general, the process of viral replication is summarised as follows:
 Adsorption of virus to host cell and entry
 Uncoating to liberate viral genome
 Synthesis and/or replication of viral DNA
 Integration of DNA into host genome
 Production and assembly of new viral particles
 Maturation
 Release of new virions
Each of this stages represents a potential site for antiviral therapy.
Figure1: Various stages in HIV infection
Infect Dis Clin North Am. 2014 Sep; 28(3): 371–402.

Figure 2: HIV lifecycle and target of the major classes of antiretroviral drugs
GOALS AND PRINCIPLES OF ANTIRETROVIRAL THERAPY
The key goals of antiretroviral therapy are to:

 achieve and maintain suppression of plasma viraemia to below the current
assays’ level of detection;
 improve overall immune function as demonstrated by increases in CD4+ T cell

count;
 prolong survival;
 reduce HIV associated morbidity;
 improve overall quality of life; and

 reduce risk of transmission of HIV to others
In order to achieve these goals, the clinicians and patients must recognize several key
principles:
 current antiretroviral regimens do not eradicate HIV, viral rebound occurs rapidly
after treatment discontinuation, followed by CD4 decline, with potential for
disease progression
 strict adherence to the prescribed regimen is essential in order to avoid viral

rebound and the potential for selection of drug resistance mutations
 a combination regimen should consist of preferably 3 (but at least 2) active

agents based on genotypic resistance test results.
Classes of Antiviral agents

There are three classes of antiviral agents:
 Antiretroviral agents
 Anti-influenzal agents
 Anti-herpes simplex agents
Antiretroviral agents
Acquired immune deficiency syndrome (AIDS) was first recognised in 1981 and it is
caused by the human immunodeficiency virus (HIV), a retrovirus which attacks T-
lymphocytes and other cells of immune system. It is called a retrovirus because its
genome is in the form of RNA, and on entering into the host cell this RNA is converted
into DNA by the viral enzyme called reverse transcriptase, which is the equivalent
enzyme to DNA polymerase. The DNA is then integrated into the host cell genome
where it resides permanently as a latent virus.
The HIV has surface proteins which acts as binding sites; these are called gp120 and
gp41. In addition, there are receptor sites on the lymphocytes surface. The main
receptor on the lymphocyte is CD4, to which the gp120 protein attaches. Other
receptors are CXCR4 or CCR5, to which the gp41 protein binds. An HIV infection of
lymphocytes requires attachment at both sites and tight attachment of the virus to the
host surface receptors leads to membrane fusion. The HIV RNA contains nine genes,
which codes for structural proteins including capsid proteins but also three key
enzymes:
 reverse transcriptase
 integrase
 protease
These enzymes provided useful targets for antiviral chemotherapy.
Nucleosides reverse transcriptase inhibitors(NRTIs)
Those nucleosides analogues acting at this target sites are referred to as NRTIs.
Zidovudine ( AZT)
 First ARV to be developed in 1987
 AZT is coverted to the trisphosphate form by cellular enzymes in both infected
and non-infected cells where it is utilised by reverse transcriptase and acts as a
chain terminator
 Well absorbed from the gut and can be taken orally
 It is associated with blood disorders
 Other members of NRTIs are didanosine, Zalcitabine and Lamivudine
Nucleotide Reverse Transcriptase Inhibitors

 They are nucleotides, which means they are already phosphorylated
 Other than that, they work the same way as NRTIs.e.g., Tenofovir
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTs)

 Another group of drugs acting on reverse transcriptase
 Their structures are completely different from nucleoside analogues
 They bind at a different site on the enzyme reverse transcriptase
 Examples include, Nevirapine and Efavirenz
Protease Inhibitors (PIs)

 PIs were first introduced in 1996
 The enzyme protease, is responsible for the modification of newly formed viral
proteins produced during viral replications
 PIs prevents post translational modification of viral proteins leading to the
production of non-infectious viral particles
 Examples include Ritonavir, saquinavir and Lopinavir
 Fortunately, PIs do not interfere with the activity of human proteases (trypsin and
pepsin)
 When used in combination with other agents, they bring about a dramatic
improvement in the clinical picture and reduction of HIV-related deaths.
 Side effects includes abnormal distribution of body fats (lipodystrophy). Caution
is needed in patients with haemophilia who are at an increase risk of bleeding.
 Examples include, ritonavir, saquinavir and lopinavir.
Fusion Inhibitors.
The HIV is an enveloped virus and has to used membrane with the host cell in order to
bring about an infection. It is known that two receptors on HIV (gp120 and gp41) bind to
host cell receptors (CD4 and CXCR4) respectively and are responsible for infection. If
these receptors could be blocked, then infection process will be stalled.
Enfurvirtide is a 36 amino acid peptide derived from HIV gp41 and inhibits gp41-
mediated fusions. It works extracellularly and has to be self-administered by
subcutaneous injection. The most common side is injection site reaction. It is synergistic
with NRTIs, NNRTIs, PIs and other antiretrovirals. Resistance can occur in the binding
area of gp41.
Maraviroc is an orally active fusion inhibitor. It is only active against viruses binding
to the CCR5 co-receptor; not CXCR4. The reason for the difference in virus receptor
binding is unclear but CXCR4 binding variants may emerge as the disease progresses.
Patients on maraviroc have been shown to CD4+ T-cells. The profile and adverse
effects is also acceptable
Integrase inhibitors
After insertion of HIV viral RNA into the host cell, the genetic materials are converted
into double stranded DNA (dsDNA) by the enzyme, reverse transcriptase produced by
the virus. This DNA is then further processed by another viral enzyme called integrase
which produces sticky ends on the DNA of virus and host. The viral DNA is then spliced
into the host DNA.
Raltegravir is an integrase inhibitor that has recently been released for clinical use
Maturation inhibitors (MIs)

Prior to release from the host cell, all newly formed HIV particles undergo a maturation
process and this is a key step in viral replication. One of the potential targets is the HIV
Gag proteins, which forms the capsid shell of the virus. MIs cause the Gag protein, and
hence the capsid, to be defective and non-infectious. These drugs have been shown to
be active against drug resistant strains of HIV.
REFERENCES
Pau AK, George JM. Antiretroviral therapy: current drugs. Infect Dis Clin North Am
2014; 28:371-402.
Scorzoni L, de Paula ESAC, Marcos CM, et al. Antifungal Therapy: New Advances in
the Understanding and Treatment of Mycosis. Frontiers in microbiology 2017; 8:36.
General Principles of Antimicrobial Therapy: Mayo Clin Proc. 2011;86(2):156-167
Zdziarski P, Simon K, Majda J. Overuse of high stability antibiotics and its
consequences in public and environmental health. Acta Microbiol Pol 2003; 52:5-13.

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Department of Pharmaceutical Microbiology,

Faculty of Pharmacy, University of Benin, Benin City.

COURSE CODE: PMB 513

Targets for antiviral agents

Infect Dis Clin North Am. 2014 Sep; 28(3): 371–402.

GOALS AND PRINCIPLES OF ANTIRETROVIRAL THERAPY

The key goals of antiretroviral therapy are to:

 improve overall immune function as demonstrated by increases in CD4+ T cell

 reduce HIV associated morbidity;

 improve overall quality of life; and

 strict adherence to the prescribed regimen is essential in order to avoid viral

 a combination regimen should consist of preferably 3 (but at least 2) active

Classes of Antiviral agents

These enzymes provided useful targets for antiviral chemotherapy.

Nucleosides reverse transcriptase inhibitors(NRTIs)

Nucleotide Reverse Transcriptase Inhibitors

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTs)

Protease Inhibitors (PIs)

Maturation inhibitors (MIs)

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