Antiviral drugs

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Antimicrobial agents
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Antiviral Drugs
Overview:
• Viruses are obligate intracellular parasites.
• They lack both a cell wall and a cell
membrane.
• They do not carry out metabolic processes.
• Viral reproduction uses much of the host's
metabolic machinery, and few drugs are
selective enough to prevent viral replication
without injury to the host.
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• Therapy for viral diseases is further
complicated by the fact that the clinical
symptoms appear late in the course of the
disease, at a time when most of the virus
particles have replicated.
• At this late, symptomatic stage of the viral
infection, administration of drugs that block
viral replication has limited effectiveness.
• However, some antiviral agents are useful as
prophylactic agents.
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Antiviral drugs
For respiratory
virus infections
For hepatic viral
infections
For herpes and
cytomegalovirus
infections
For HIV
infections
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Welcome back
LAST LECTURE!!

Treatment of Respiratory Virus
Infections
• Viral respiratory tract infections for which
treatments exist include those of influenza A
and B and respiratory syncytial virus (RSV).
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A. Neuraminidase inhibitors
• Orthomyxoviruses that cause influenza
contain the enzyme neuraminidase, which is
essential to the life cycle of the virus, and that
can be selectively inhibited by the sialic acid
analogs, oseltamivir and zanamivir.
• These drugs prevent the release of new virions
and their spread from cell to cell.
• Oseltamivir and zanamivir are effective against
both Type A and Type B influenza viruses.
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• Administered prior to exposure,
neuraminidase inhibitors prevent infection,
and when administered within the first 24 to
48 hours after the onset of infection, they
have a modest effect on the intensity and
duration of symptoms.
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Mechanism of action:
• Influenza viruses use a specific neuraminidase
that is inserted into the host cell membrane to
release newly formed virions.
• Oseltamivir and zanamivir are analogs of the
sialic acid substrate and serve as inhibitors of
the enzyme activity.
• Virions accumulate at the internal infected cell
surface.
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Resistance:
• Through mutations of the neuraminidase.
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B. Inhibitors of viral uncoating
(Amantadine derivatives)
• Amantadine and rimantadine.
• The therapeutic spectrum of the adamantine
derivatives, is limited to influenza A infections,
in both treatment and prevention.
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• Their primary antiviral mechanism is to block
the viral membrane matrix protein, M2, which
functions as a channel for hydrogen ion. This
channel is required for the fusion of the viral
membrane with the cell membrane that
ultimately forms the endosome.
• These drugs may also interfere with the
release of new virions.
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Resistance:
• Resistance has been shown to result from a
change in one amino acid of the M2 matrix
protein.
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Note:
• Amantadine and rimantadine should be used
with caution in pregnant and nursing mothers.
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C. Ribavirin
• Ribavirin is a guanosine analog.
• It is effective against a broad spectrum of RNA
and DNA viruses.
• Used in treating infants and young children
with severe RSV infections.
• Also effective in chronic hepatitis C infections
when used in combination with interferon-α-
2b.
• May reduce the mortality and viremia of Lassa
fever.
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• The mechanism of action of ribavirin has been
studied only for the influenza viruses.
• The drug is first converted to the 5'-phosphate
derivatives, the major product being ribavirin-
triphosphate, which inhibits guanosine
triphosphate formation, preventing viral
mRNA capping, and blocking RNA-dependent
RNA polymerase.
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Notes:
• Absorption is increased if the drug is taken
with a fatty meal.
• Ribavirin is contraindicated in pregnancy
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Corona Virus
• Preferred therapies (in order of preference):
• Nirmatrelvir with ritonavir (Paxlovid);
• Sotrovimab ;
• Remdesivir
• Alternative therapies (in alphabetical order):
• Bebtelovimab;
• Molnupiravir
Antimicrobial agents 24

Treatment of Hepatic Viral Infections
• The hepatitis viruses thus far identified ”A, B,
C, D, and E” each has a pathogenesis
specifically involving replication in and
destruction of hepatocytes.
• Hepatitis B and hepatitis C are the most
common causes of chronic hepatitis, cirrhosis,
and hepatocellular carcinoma and are the only
hepatic viral infections for which therapy is
currently available.
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• Chronic hepatitis B is usually treated with
peginterferon-α-2, Oral therapy includes
lamivudine, adefovir or entecavir.
• The FDA approval of sofosbuvir in 2013
changed the standard treatment of hepatitis C
from peginterferon-α-2b plus ribavirin to
sofosbuvir and the newly discovered drugs.
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A. Interferon
• Interferon is a family of naturally occurring,
inducible glycoproteins that interfere with the
ability of viruses to infect cells.
• The interferons are synthesized by
recombinant DNA technology. At least three
types of interferon exist, α, β, and γ.
• One of the interferon-α glycoproteins:
interferon-α-2b has been approved for
treatment of hepatitis B and C and cancers. 36

• It appears to involve the induction of host cell
enzymes that inhibit viral RNA translation,
ultimately leading to the degradation of viral
mRNA and tRNA.
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Adverse effects:
• Include flu-like symptoms.
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B. Lamivudine
• This cytosine analog is an inhibitor of both
hepatitis B virus (HBV) DNA polymerase and
human immunodeficiency virus (HIV) reverse
transcriptase.
• Lamivudine must be phosphorylated by host
cellular enzymes to the triphosphate (active)
form.
• This compound competitively inhibits HBV
DNA polymerase.
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C. Entecavir
• Entecavir is a guanosine analog for the
treatment of HBV infections.
• Fffective against lamivudine-resistant strains
of HBV.
• Following intracellular phosphorylation to the
triphosphate, it competes with the natural
substrate, deoxyguanosine triphosphate, for
viral reverse transcriptase.
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Phosphorylation
Entecavir triphosphate form
(competes with deoxyguanosine
triphosphate for viral reverse
transcriptase)
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D. Adefovir
• Adefovir dipivoxil is a nucleotide analog.
• It is phosphorylated to adefovir diphosphate,
which is then incorporated into viral DNA. This
leads to termination of further DNA synthesis
and prevents viral replication.
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Adefovir Adefovir diphosphate
Incorporation
Termination of DNA synthesis Viral DNA
& prevents viral replication
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FDA approved drugs for hepatitis C
• Mavyret (glecaprevir/pibrentasvir)
• Vosevi
(sofosbuvir/velpatasvir/voxilaprevir)
• Epclusa (sofosbuvir/velpatasvir)
• Zepatier (elbasvir/grazoprevir)
• Daklinza (daclatasvir)
• Harvoni (ledipasvir, sofosbuvir)
• Sovaldi (sofosbuvir)

Protease inhibitors
• The viral serine protease is crucial for processing the
single polyprotein encoded by HCV RNA into individually
active proteins.
• Without these serine proteins, RNA replication does not
occur and the HCV life cycle is effectively disrupted.
• They end in “previr”, e.g., grazoprevir, voxilaprevir and
glecaprevir.

Polymerase inhibitors
• There are two types of RNA polymerase inhibitors:
1) nucleoside/nucleotide analogs that compete for the
enzyme active site, e.g. Sofosbuvir
2) non-nucleoside analogs that target allosteric sites, e.g.,
dasabuvir
• These inhibitors often end in “-buvir.”

Replication complex inhibitors
• They include ledipasvir, elbasvir, velpatasvir,
pibrentasvir, and daclatasvir.
• They often end in “-asvir.”
• With the exception of daclatasvir, these agents are all
coformulated with other direct-acting antivirals.

• Ribavirin + pegylated interferon or one of the
antivirals

Herpes viruses treatement
• Herpesviruses have the property of being
latent, in a potentially viable form, within the
cells of the host after primary infection.
• Latent virus persists for long periods of time,
probably throughout life: some reactivate
from time to time from the latent state to
produce recurrent infection.

They constitute a large family including:
• Herpes simplex 1 and 2 (HSV); the cause of fever
blisters and genital infections,
• Varicella-zoster virus (VZV); the cause of
chickenpox and shingles,
• Epstein-Barr virus (EBV); associated with infection
of the lymphoid tissue,
• Cytomegalovirus (CMV); infects the salivary
glands and other viscera,
• Human herpesviruses-6 and -7 (HHVs); cause
roseola,
• Herpesvirus-8 (KSHV); implicated in Kaposi’s
sarcoma.
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Treatment of Herpesvirus Infections
• All are purine or pyrimidine analogs that
inhibit viral DNA synthesis.
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A. Acyclovir
• Herpes simplex virus (HSV) Types 1 and 2,
varicella-zoster virus (VZV), and some Epstein-
Barr virus mediated infections are sensitive to
acyclovir.
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• Acyclovir, a guanosine analog, is
monophosphorylated in the cell by the herpes
virus thymidine kinase. Therefore, virus-infected
cells are most susceptible.
• The monophosphate analog is converted to the
di- and triphosphate forms by the host cells.
• Acyclovir triphosphate inhibits viral DNA
polymerase and the monophosphate form is
incorporated into the viral DNA, causing
premature DNA-chain termination
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Resistance:
• Altered or deficient thymidine kinase and DNA
polymerases.
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B. Valaciclovir
• Valaciclovir or valacyclovir is the valyl ester of
acyclovir and is used in the management
of herpes simplex and herpes
zoster (shingles).
• It is a prodrug, rapidly hydrolysed in vivo by
esterases to acyclovir.
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Mechanism of action???
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C. Ganciclovir
• Ganciclovir is an analog of acyclovir with
greater activity against CMV the only viral
infection for which it is approved.
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• Like acyclovir, ganciclovir is activated through
conversion to the nucleoside triphosphate by
viral and cellular enzymes.
• The nucleotide competitively inhibits viral
DNA polymerase and can be incorporated into
the DNA, thereby decreasing the rate of chain
elongation
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Human immunodeficiency virus
(HIV)
• HIV causes acquired immunodeficiency
syndrome (AIDS), a condition in humans in
which the immune system begins to fail,
leading to life-threatening opportunistic
infections.
• Most untreated people infected with HIV-1
eventually develop AIDS. These individuals
mostly die from opportunistic infections
or malignancies associated with the
progressive failure of the immune system. 73

• Treatment with anti-retrovirals increases the
life expectancy of people infected with HIV.
• There are five classes of antiretroviral drugs,
each of which targets one of four viral
processes.
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• These classes of drugs are:
- nucleoside and nucleotide reverse transcriptase
inhibitors (NRTIs)
- non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
- protease inhibitors
- entry inhibitors
- the integrase inhibitors.
• The current recommendation for primary
therapy is to administer two NRTIs with either a
protease inhibitor or an NNRTI. 76

Nrtis Used to Treat HIV Infection
• Overview:
Examples: Zidovudine (azidothymidine),
stavudine, didanosine, lamivudine, zalcitabine
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• (NRTIs) are analogs of native ribosides lacking a
3'-hydroxyl group. Once they enter cells, they are
phosphorylated by cellular enzymes to the
corresponding triphosphate analog, which is
preferentially incorporated into the viral DNA by
virus reverse transcriptase. Because the 3'-
hydroxyl group is not present, a 3'-5'-
phosphodiester bond between an incoming
nucleoside triphosphate and the growing DNA
chain cannot be formed, and DNA chain
elongation is terminated. 79

Resistance:
• Through mutation of reverse transcriptase.
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NNRTIs Used to Treat AIDS
• Examples: Nevirapine, Delavirdine, Efavirenz.
• They are noncompetitive inhibitors of HIV-1
reverse transcriptase. They bind to HIV reverse
transcriptase at a site adjacent to the active
site, inducing a conformational change that
results in enzyme inhibition. They do not
require activation by cellular enzymes. 82

HIV Protease Inhibitors
• Examples: Ritonavir , Saquinavir.
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• These drugs are reversible inhibitors of the
HIV aspartyl protease the viral enzyme
responsible for cleavage of the viral
polyprotein into a number of essential
enzymes (reverse transcriptase, protease, and
integrase) and several structural proteins.
• The inhibition prevents maturation of the
viral particles and results in the production of
non-infectious virions.
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Resistance:
• Occurs as an accumulation of stepwise
mutations of the protease gene.
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Entry Inhibitors
A. Enfuvirtide
• Enfuvirtide is a fusion inhibitor.
• For HIV to gain entry into the host cell, it must
fuse its membrane with that of the host cell.
This is accomplished by changes in the
conformation of the viral transmembrane
glycoprotein gp41, which occurs when HIV
binds to the host cell surface. Enfuvirtide
binds to gp41, preventing the conformational
change. 87

B. Maraviroc
• Maraviroc blocks the CCR5 coreceptor that
works together with gp41 to facilitate HIV
entry through the membrane into the cell.
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Integrase Inhibitors
A. Raltegravir :
• It specifically inhibits the final step in
integration of the viral DNA into our own host
cell DNA.
B. Elvitegravir (EVG):
• is an investigational new drug for the
treatment of HIV infection. It acts as
an integrase inhibitor.
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May God bless everyone with the best
of health
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Thank You
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Antiviral drugs

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