Video summary
This video focuses on antiviral pharmacology specifically targeting RNA viruses, highlighting established treatments for influenza and hepatitis C while noting that therapies for other viral types are still under development. The discussion begins with the influenza virus, detailing its structural components such as hemagglutinin, which facilitates attachment to host cells; neuraminidase, an enzyme responsible for releasing new virions from infected cells; and the M2 channel, a proton pore essential for uncoating the viral RNA inside the cell. The replication process involves an RNA-dependent RNA polymerase that synthesizes viral RNA within the cytoplasm without needing a DNA template. Consequently, antiviral strategies primarily target these specific mechanisms to halt infection progression before significant cellular damage occurs.
For influenza treatment, neuraminidase inhibitors like oseltamivir, zanamivir, and peramivir are the standard of care because they block the release of new virus particles from host cells. Oseltamivir is widely used as an oral prodrug effective against both Influenza A and B strains, including avian (H5N1) and swine flu variants, but must be administered within 48 hours of symptom onset to maximize efficacy before the viral load peaks. Zanamivir serves as a crucial alternative for cases resistant to oseltamivir; however, it is delivered via inhalation powder rather than orally due to poor bioavailability, making it contraindicated for asthmatic patients because of the risk of bronchospasm. Peramivir offers an intravenous option suitable for hospitalized patients, while older M2 channel blockers like amantadine and rimantadine are no longer recommended due to widespread viral resistance.
The video then shifts focus to hepatitis C virus (HCV), contrasting outdated combination therapies involving interferon alpha and ribavirin with modern directly acting antivirals that offer shorter treatment durations and higher cure rates. HCV replication relies on a polyprotein complex synthesized in the cytoplasm, which must be cleaved by specific proteases into functional structural and non-structural proteins to assemble new viruses. Directly acting antivirals interrupt this process through three main classes: NS3/4A protease inhibitors (ending in -previr) that prevent protein cleavage; NS5B polymerase inhibitors (ending in -buvir) that stop RNA synthesis by targeting the viral RNA-dependent RNA polymerase; and NS5A inhibitors (ending in -asvir) which disrupt viral assembly and replication complex formation.
Effective management of hepatitis C requires using these directly acting antivirals exclusively in combination regimens to minimize the emergence of drug-resistant strains, rather than as monotherapy. While interferon alpha stimulates host immune responses like cytotoxic lymphocyte activity through the JAK-STAT pathway, its use has diminished alongside newer agents; ribavirin remains a component in some older or specific protocols but functions primarily by inhibiting viral RNA polymerase after cellular phosphorylation and depleting GTP pools to hinder replication. Ribavirin is also utilized off-label for respiratory syncytial virus infections in immunocompromised children, though it carries significant side effects such as dose-dependent hemolytic anemia and bone marrow suppression that require careful monitoring during treatment.
Read the full video transcript
Hello everyone. In this video we will
talk about antiviral drugs for RNA
viruses. In the previous video we've
already discussed the antiviral drugs
for DNA viruses. You can watch that
video as well.
So in RNA viruses we have the positive
sense single stranded RNA viruses,
negative sense single stranded RNA
viruses, and double stranded RNA
viruses. Now we will focus on hepatitis
C virus and influenza virus because
these are the viruses for which the
drugs are available and in fact used for
other viruses as well the drugs are
being developed but the efficacy has not
been proven. So for influenza and
hepatitis C virus the drugs are
established and that we are going to
discuss in this video.
So when we talk about influenza virus we
will know little bit about the structure
as well so that we understand the drugs
better.
So this influenza virus has a
coat and on this coat are present
certain proteins that is neuraminidase
and hemagglutinin and they have
different functions where this
hemagglutinin protein is important for
attachment of the virus to the host
cell. So here we are seeing
hemagglutinin is responsible for
attachment of the virus to the host cell
and hence entry of the virus. Then on
this membrane we also have M2 channel
through which hydrogen ions enter into
the virus and this is responsible for
uncoating of the virus. Okay, so
uncoating actually inside there will be
RNA. So this RNA should come out for
that there should be uncoating so that
the membrane is removed so that is
brought about by entry of the hydrogen
ions. So that is another then
within the virus we have one enzyme that
is the RNA dependent RNA polymerase and
this is responsible for synthesis of RNA
of the virus. Okay? So, normally we see
that RNA is synthesized from DNA. Here
we have a polymerase which uses RNA as
the template. So, that is why the name
RNA-dependent RNA polymerase. And from
this, the RNA is replicated also. And
there is translation of RNA into
proteins as well.
So, these proteins which are
synthesized, basically the membrane
proteins are synthesized. So, when the
RNA is replicated and the protein which
is synthesized, they assemble together
and they again move out of the host
cell. So, this moving out of the host
cell is by neuraminidase enzyme. Okay?
So, we have seen the functions of the
different proteins. That is the
hemagglutinin, neuraminidase, and the M2
channel. So, let us see what are the
drugs available for the influenza virus.
Well, the commonly used drug include the
neuraminidase
inhibitors. Okay? So, this is
neuraminidase inhibitor. And in these
drugs, we have oseltamivir, zanamivir,
and peramivir.
So, among this, oseltamivir is the most
commonly used drug. Okay? And it is a
prodrug. And prodrug means that the drug
is going to have high oral
bioavailability.
So, this oseltamivir is used for
influenza, both influenza A virus,
influenza B virus. It is also used for
bird flu virus, that is H5N1, and the
swine flu virus, that is H1N1.
And it is used both for patients and
also for post-exposure prophylaxis.
And we have to ensure early initiation
of the therapy. That is within 48 hours.
Why? Because you see that here it is
blocking the release of the RNA virus
from the host cell. So, first it is
multiplying within the cell. So, this
multiplication of the virus within the
host cell is maximum within the first 48
hours.
So, for this drug to act effectively, it
is important that it is given within the
first 48 hours. Otherwise, the maximum
damage to the host cells would already
have been done.
Then the next drug is zanamivir.
Zanamivir is not given orally because it
has very low oral bioavailability and it
is given by inhalation as a powder.
But because it is used as powder form,
it can cause bronchospasm and that is
why it is contraindicated in asthma
patients.
So, when is this zanamivir used? Well,
oseltamivir is the most common drug
used, but there may be influenza virus
which is resistant to oseltamivir. So,
this drug, zanamivir, is used for
oseltamivir-resistant
cases.
Then the third drug for this
neuraminidase inhibitors is peramivir,
which can be given IV. So, in
hospitalized patients also, we have now
another drug that is peramivir, which is
given IV.
Then we have other drugs, that is the M2
channel blockers. So, I told you before
that via the M2 channel, hydrogen enters
into the virus and is responsible for
the uncoating of virus and release of
the RNA, which then uses the host
machinery for translation and
replication.
So, there are drugs which block this M2
channel and these include amantadine and
rimantadine. Now, these drugs were used
before, but now they are not used
because the influenza virus has been
found to be now resistant to this
amantadine and rimantadine. So, now the
drugs which are used is neuraminidase
inhibitors.
Now, moving on to the next virus, that
is the hepatitis C virus.
Now, for hepatitis C,
before we had this combination therapy,
that is interferon alpha given with
ribavirin.
So, ribavirin is actually a nucleoside
analog that we have seen in acyclovir in
the previous video as well. That was
also a nucleoside analog, and whenever
we talk about nucleoside analog, then
that drug needs phosphorylation within
the cell. Okay? So, this ribavirin also
is a nucleoside analog, but it was given
along with interferon alpha. Now,
this was a very long-term therapy. It
required like 24 weeks to 48 weeks of
treatment. But, now better drugs have
come against hepatitis C virus, that is
the directly acting antiviral, for which
the duration of treatment is much
lesser, and cure rate is also better.
So, first we will see these directly
acting antivirals. What are these
directly acting antivirals?
So, this hepatitis C virus, again,
it is a RNA virus, and as it enters into
the cell, the RNA is released from the
virus, and then there is transcription
of this virus using the host machinery,
that is the ribosomes of the host are
used within the cytoplasm, and there is
synthesis of a polyprotein complex. What
is polyprotein? Polyprotein is basically
a combination of lot of proteins. Let us
see here. So, here you see this is the
polyprotein, where we see that whole
protein is synthesized, which is having
within itself structural proteins. So,
this is 1 2 3 4 different different
structural proteins are there, and there
are also non-structural proteins. So,
these non-structural proteins NS2, NS3,
NS4A, NS4B, NS5A, NS5B. Okay? So, NS is
for non-structural.
Now,
we have drugs which prevent the cleavage
of this polyprotein which is
synthesized. Okay? So, here this
polyprotein is synthesized and then it
is cleaved by proteases. So there is
NS34A protease which cleaves this
polyprotein complex and releases the
different proteins. Some become the
structural proteins like on the
envelope, others become the functional
proteins. So only after cleavage can the
virus assemble and there can be
replication of the virus, right? Now if
you prevent this polyprotein cleavage,
then the proteins will not be released.
There will not be any replication of the
virus, right? So for this we have NS34A
inhibitors. Actually, these are NS34A
protease inhibitors.
And they prevent the cleavage of this
polyprotein. So we will see when we will
talk about
HIV. There also we have this protease
inhibitors which prevent the cleavage of
polyprotein which is synthesized. So for
HIV also similar mechanism exists.
Polyprotein is synthesized and that is
broken down. So in HCV also we have
similar protease inhibitors, NS34A
protease inhibitors. And these include
telaprevir, boceprevir, simeprevir. And
how to remember this? See, they are
having this term previr. Previrs what?
Previrs basically PR for protease. So
these are protease inhibitors, okay?
So that is first class of this directly
acting antiviral.
Then we have second class that is NS5B
inhibitors. NS5B inhibitors. So they
inhibit this particular non-structural
protein. And this protein basically is
RNA-dependent RNA polymerase. So I told
you that these are all non-structural
proteins. NS wherever it is written,
these are non-structural proteins. So it
is having some functional component. So
that is the enzyme, RNA-dependent RNA
polymerase. So this enzyme is inhibited.
So this is NS5B inhibitor. So basically
they are inhibiting the RNA-dependent
RNA polymerase only, but here, because
it is from the polyprotein complex, that
is why here they are named as NS5B
inhibitors. What are these drugs? These
are sofosbuvir and dasabuvir. So, here,
this the B which is coming, that is for
the
NS5B inhibitors. Okay?
Then, we have the NS5A inhibitors. So,
these inhibit the NS5A protein, and
these proteins are important for viral
assembly and also for formation of the
replication complex. Okay? See, whenever
the replication is going on, replication
means synthesis of new genome is going
on. In that case, first replication
complex should form. So, for that also,
we need certain proteins. So, NS5A
inhibitors inhibit these proteins.
And these are the drugs which are ending
in -asvir, -asvir. Okay? So, NS3/4
inhibitors, they are -previr. NS5B
inhibitors are -buvir, and NS5A
inhibitors are -asvir. Okay? So, this A,
-asvir, is for NS5A inhibitors. Okay?
So, those were the directly acting
antiviruses. Now,
we have some recommendations for the use
of these directly acting antivirals.
First of all, they are never used alone.
They are always used in combination.
Okay? Because this decreases the chances
of emergence of resistance. So,
NS5B, remember. NS5B is always used in
combination either with NS3/4A. So, here
we are having simeprevir plus
sofosbuvir, and here we are having NS5B
in combination with NS5A. So, NS5B is
always in combination either with NS3/4A
or NS5A inhibitors. Okay? So, that is is
thing.
Then, we also have NS34A inhibitor in
combination with ribavirin and
interferon alpha. So, this I told you,
ribavirin and interferon alpha was used
before, and it was given for very long
term. But, with simeprevir given with
ribavirin and pegylated interferon
alpha, the duration is less and cure
rate is more.
Then, even this sofosbuvir can be given
along with ribavirin plus pegylated
interferon alpha. Okay? So, first thing
is that NS5B inhibitors are always used
either in combination with NS34A or NS5A
inhibitors or ribavirin and pegylated
interferon alpha. And similarly, NS34A,
either you combine with NS5B, which we
have already seen, or it can be given
along with ribavirin and interferon
alpha. Right? So, those are the
recommendations. Now, moving on to the
other drugs, that is ribavirin and
interferon alpha. Interferon alpha, I'm
not going to discuss what is the
mechanism of action because I've already
discussed in the previous video. Because
these interferons are actually released
from the host cells, these are the
normal immune mechanisms which exist in
the body. But, when we are giving
interferon alpha from outside, it acts
by the same mechanism. It just
stimulates the JAK-STAT pathway and
causes release of certain cytokines and
also makes the cells which is infected
with virus more susceptible for death by
cytotoxic lymphocytes. Okay? So,
cytotoxic lymphocytes will be able to
identify the cells better, the infected
cells better, and they will be able to
kill it. So, I would suggest that you go
back to the video on antiviral drugs for
DNA viruses, and there you will get the
mechanism of action of interferons along
with some side effects as well.
So, here we will talk about ribavirin.
So, ribavirin, as I already told you, it
is a nucleoside analog. And like all
nucleoside analogs which we have seen
before also in our previous video, that
they need phosphorylation. So, ribavirin
is phosphorylated thrice, okay? So,
three phosphate groups are attached. And
then, only after phosphorylation, it can
inhibit the RNA polymerase so that the
replication is not possible. And it also
depletes the GTP pools so that the
nucleotides are not available to be
incorporated into the RNA, right?
So, what are the uses of ribavirin?
Well, it is used in hepatitis C, as I
told you, but it is used in our in
combination with NS3/4A inhibitors or
with NS5B inhibitors.
And it can also be used in respiratory
syncytial virus in infants and children.
Though not much effect has been found,
but it's still it is being recommended
for use in immunocompromised infants and
children, okay? So, it is used as
nebulized ribavirin.
What are the side effects? Side effects
include dose-dependent hemolytic anemia.
So, as the dose is increased, there are
increased chances of hemolytic anemia.
And bone marrow depression occurs. Plus,
there are certain CNS and GI symptoms as
well.
So, that was about the drugs which are
used for influenza and hepatitis C
virus. Thanks for watching the video. If
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Physiology Open. Thank you.