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.