In this lecture we’re gonna cover the pharmacology
of antiviral drugs so let’s get right into it.
Antivirals are a large and diverse group of
agents that are typically classified by the
virus infections for which they are used.
For simplicity we can divide them into 4 groups that is; (1) Anti-influenza drugs, (2) Anti-HIV drugs,
(3) Anti-hepatitis drugs, and (4) Anti-herpes
drugs.
Now, lets discuss these one by one starting
with anti-influenza drugs.
So, influenza is an enveloped virus with a
genome made up of single-stranded, segmented RNA.
The viral envelope is made up of a lipid bilayer
that contains three of the viral transmembrane
proteins: hemagglutinin (HA), neuraminidase
(NA), and matrix 2 (abbreviated as M2).
The first step of the influenza virus infection
involves binding of hemagglutinin
to sialic acid residues on the surface of host cell,
which results in engulfment of the virus
into the cell via endocytosis.
Next, the membrane protein M2 forms pH-gated
channels that allow protons to move through
the viral envelope and acidify the core of
the virus, causing release of the viral RNAs
and proteins, which are then transported into
the cell nucleus.
In the nucleus viral RNA is transcribed into
messenger RNA.
The translation of mRNA into viral proteins
takes place in ribosomes in the cytoplasm.
Once synthesized, hemagglutinin and neuraminidase
glycoproteins are secreted through
the Golgi apparatus onto the cell surface where they
fuse with the plasma membrane, whereas other
viral proteins migrate back to the nucleus,
where they assemble with newly replicated genomes.
Assembled viral capsid then moves to the plasma
membrane where it buds off, taking a segment
of membrane containing the haemagglutinin
and neuraminidase, and thus forming a viral particle.
In the last step of the replication, viral
neuraminidase (NA) enzyme cleaves and removes
sialic acid receptors from the surface of
the cell, thereby allowing release and spread
of the virus to new cells.
Now, there are three classes of approved drugs
for influenza.
The first one are M2 ion channel inhibitors,
which work simply by blocking the M2 channel
and thereby restricting passage of protons
which are required to trigger the release
of viral genes into the host cell.
Drugs that belong to this class include Amantadine
and Rimantadine.
Now, moving on to the next class, which actually
represents a new class of anti-influenza agents,
called endonuclease inhibitors.
At this time, the only agent in this class
is a drug called Baloxavir, which works by
selectively inhibiting cap-dependent endonuclease,
a key enzyme involved in the initiation of
influenza virus mRNA synthesis.
By blocking this enzyme, Baloxavir prevents
viral gene transcription and ultimately influenza
virus replication.
Finally, moving on to the third class of influenza
drugs that is neuraminidase inhibitors.
The agents in this class exert their antiviral
activity by inhibiting the viral neuraminidase
enzyme found on the surface of the viral particle.
Without active neuraminidase, the virus is
unable to cleave sialic acid and unable to
escape from the cell.
Drugs that belong to this class include Oseltamivir,
Peramivir, and Zanamivir.
Now, let’s move on to our next group of
antivirals, that is Anti-HIV drugs.
So, HIV or human immunodeficiency virus is
composed of three main layers; the envelope
containing surface proteins gp120 and gp41;
the viral matrix, containing protease enzymes;
and the core containing viral capsid encasing
two copies of RNA and enzymes
such as reverse transcriptase and integrase.
The main target of HIV is the CD4+ T lymphocytes,
which are essential regulators of the immune system.
The first step of HIV infection involves sequential
binding of the gp120, first to CD4 receptor,
and then to human co-receptor, either CCR5
or CXCR4.
This binding enables the viral envelope to
fuse with the host cell membrane, allowing
viral capsid to enter the host cell's cytoplasm.
During uncoating, the single-stranded RNA
genomes within the capsid are released into
the cytoplasm where the enzyme reverse transcriptase
converts the virus RNA into double-stranded DNA.
Next, the integrase enzyme binds to the viral
DNA, transports it into the nucleus, and inserts
it into the host cell's DNA.
Using the host cellular system, copies of
HIV genomic RNA as well as shorter strands
of messenger RNA are constructed and then
transported out of the nucleus.
In the cytoplasm mRNA is translated by the host
cell's ribosomes to viral proteins that undergo
modification and cleavage by HIV protease
enzymes.
Finally, the resulting structural proteins
and replication enzymes assemble with viral
genomic RNA to form new virions, which then
bud off of the host cell, thus creating new
viruses capable of infecting other cells.
Now, there are several classes of HIV drugs,
each designed to block the virus at specific
stage of the replication cycle.
So let’s discuss these one by one starting
with entry inhibitors.
This class of drugs interferes with the binding,
fusion and entry of an HIV virion to a CD4 cell.
Currently we have three drugs that belong
to this class, each with its own unique mechanism of action.
The first one, Enfuvirtide works by binding
to the viral protein gp41 and thereby preventing
fusion with the CD4 membrane.
The second agent, Maraviroc works by binding
to the human chemokine receptor CCR5 and preventing
interaction with the viral protein gp120 thereby
inhibiting the virus from entering the cell.
And lastly the third agent, Ibalizumab, is
a monoclonal antibody that binds to the CD4
receptor and leads to conformational changes
that prevent gp120-CD4 complex from interacting
with CCR5 or CXCR4, thereby inhibiting viral
entry and fusion.
Now, moving on to the next class of HIV drugs
that is reverse transcriptase inhibitors.
Drugs in this class are divided into competitive
and noncompetitive inhibitors.
Nucleoside reverse transcriptase inhibitors
(abbreviated NRTIs) are structural analogues
of nucleic acids that competitively inhibit
reverse transcription by causing chain termination
after they have been incorporated into viral
DNA.
Drugs that belong to this group include Abacavir,
Emtricitabine, Lamivudine, Tenofovir, and Zidovudine.
On the other hand we have non-nucleoside reverse
transcriptase inhibitors (abbreviated NNRTIs),
which bind to and denature reverse transcriptase
enzyme, thus causing non-competitive inhibition.
Drugs that belong to this group include Doravirine,
Efavirenz, Etravirine, Nevirapine, and Rilpivirine.
Now, moving on to the next class of HIV drugs
that is integrase inhibitors.
This class of drugs prevents HIV from integrating
its genetic material into the host cell DNA
by specifically blocking the action of the
viral integrase enzyme.
Drugs in this class include Dolutegravir and
Raltegravir.
Finally moving on to our last class of HIV
drugs that is protease inhibitors.
Drugs in this class, work by blocking the
action of HIV protease enzyme, thus preventing
cleavage of viral polyproteins into active
proteins that are needed for the assembly
of new viral particles.
Drugs that belong to this group include Atazanavir,
Darunavir, Fosamprenavir, Ritonavir, Saquinavir, and Tipranavir.
Now, let’s move on to our next group of
antivirals that is anti-hepatitis drugs.
There are several types of viruses that primarily
attack the liver with hepatitis B virus and
hepatitis C virus being the most common causes
of hepatitis for which therapy is currently available.
So let’s discuss these in more detail starting
with hepatitis B virus.
The hepatitis B virus obtains entry into hepatocytes
by binding to the receptor called sodium taurocholate
co-transporting polypeptide (NTCP for short).
In the cytoplasm, the nucleocapsid is uncoated
at the nuclear membrane and relaxed circular
viral DNA (rcDNA) is released into the nucleus.
Within the nucleus, the relaxed circular DNA
is converted into a covalently closed circular
double-stranded DNA (cccDNA), which then serves
as the template for transcription of the subgenomic
and pregenomic RNAs.
Next, pregenomic RNA gets translated into
viral proteins including core and polymerase proteins,
which then are assembled along with
the single strand of pregenomic RNA to form nucleocapsid.
By using RNA as a template, the negative DNA
strand of the viral genome is generated through
the process of reverse transcription.
The negative DNA strand then serves as the
primer for the synthesis of the positive DNA strand.
After completion of the positive strand synthesis,
the resulting relaxed circular DNA can either
be enveloped in endoplasmic reticulum and
secreted as progeny virions or be recycled
back to the nucleus for covalently closed
circular DNA amplification.
The infected cells also secrete hepatitis
B core and envelope antigens that promote
immune tolerance and persistent infection.
Now, all currently approved antiviral drugs
for the treatment of chronic hepatitis B virus
infection are nucleoside and nucleotide analogues,
and include agents such as Entecavir, Lamivudine,
Adefovir, Telbivudine, and Tenofovir.
These drugs inhibit multiple functions of
the hepatitis B virus polymerase by competing
with natural substrates for incorporation
into developing viral DNA strand.
This results in chain termination and thus
inhibition of reverse transcription and synthesis
of the viral DNA.
Now moving on to hepatitis C virus.
So hepatitis C virus enters hepatocytes via
receptor-mediated endocytosis.
After membrane fusion and uncoating, the positive,
single-stranded viral RNA is released into
the cytosol, and then transported to the rough
endoplasmic reticulum (ER) where it serves
as a template for the viral polyprotein synthesis.
Once synthesized, the viral polyprotein is
processed by proteases such as NS3-4A serine
protease, which cleaves four non-structural
sites to generate the mature proteins that
form a complex and initiate replication.
Two of these proteins are important targets
of anti-hepatitis C drugs; The non structural
protein 5A (NS5A), which regulates the replication
of the hepatitis C viral RNA, and non structural
protein 5B (NS5B), which serves as the RNA-dependent
RNA polymerase that produces negative-sense
RNA intermediates that are then used to create
numerous copies of the positive-sense viral RNA.
Finally, newly replicated viral RNA is encased
between membranes derived from lipid droplets
and endoplasmic reticulum, and then released
from the infected cell by exocytosis.
Now, current hepatitis C treatments are made
up of combinations of drugs called direct-acting
antivirals that are classified into three
groups.
The first group includes the inhibitors of
NS3/4A protease.
Drugs that belong to this group are Boceprevir,
Glecaprevir, Grazoprevir, Paritaprevir, Simeprevir,
Telaprevir, and Voxilaprevir.
The second group includes the inhibitors of
NS5A.
Drugs that belong to this group are Daclatasvir,
Elbasvir, Ledipasvir, Ombitasvir, Pibrentasvir,
and Velpatasvir.
And finally the third group includes the inhibitors
of NS5B polymerase.
Drugs that belong to this group are Dasabuvir
and Sofosbuvir.
Now, before we move on I wanted to briefly
mention one more treatment option for hepatitis,
which involves the use of man-made interferons.
Interferons are a family of naturally occurring
proteins that interfere with the ability of
viruses to infect cells by producing an array
of antiviral effects, such as blocking viral
protein synthesis and inducing viral RNA mutagenesis.
By using recombinant DNA techniques and cell
tissue cultures, specific interferons can
be synthesized to treat hepatitis.
Examples are PEGylated interferons α-2a and
α-2b.
Use of these interferons is often paired with
a drug called Ribavirin, which enhances their
efficacy in treatment of chronic hepatitis
C.
Now moving on to our last group of antivirals
that is anti-herpes drugs.
In order to understand the mechanism of action
of these agents, first we need to briefly
review the steps of DNA synthesis during replication
of herpes virus.
So during DNA replication, first, nucleosides
must be phosphorylated into their active triphosphate form.
For example, Thymidine is sequentially phosphorylated
to mono-phosphate, di-phosphate and tri-phosphate,
and only then DNA polymerase can incorporate
it into the growing chain.
Now, the herpes virus has a number of unique
enzyme systems to drive these reactions, among
them a viral thymidine kinase, which in this
example, phosphorylates thymidine to yield
thymidine monophosphate.
In addition to that, this viral thymidine
kinase happens to recognize anti-herpes drugs
that structurally resemble guanosine nucleoside.
These drugs include Acyclovir, Ganciclovir,
and Penciclovir.
Specifically, viral thymidine kinase adds
a phosphate group to these drugs molecules,
which then allows other cellular kinases to
add two more phosphate groups, thereby producing
triphosphate substrates for the viral DNA
polymerase enzyme.
These triphosphate products then inhibit DNA
polymerase by competing with natural nucleotides
or they end up being incorporated into the
elongating DNA, leading to chain termination.
Other anti-herpes drugs that are commonly
used such as Valacyclovir, Valganciclovir,
and Famciclovir are just prodrug forms of
the other three, designed to improve bioavailability.
And with that I wanted to thank you for watching
I hope you enjoyed this video and as always
stay tuned for more.
