lecture ٢٢ - humsc

microbiologyYaqeen scientific Team

Done by:Malek al-tamimi

Lecture ٢٢

SCIENTIFIC TEAM 1 – الفريق العلمي

بسم الله الرحمن الرحيم

Anti-viral Drugs

❖ Anti-viral drugs

▪ For the antiviral drugs we are going to do like a a quick review of some of the

concepts that we have already covered in the previous lectures

▪ Viruses have no cell wall and made up of nucleocapsid.

▪ The simplest form of the virus is nucleocapsid where the genetic material is

encoded by a protein which we call the capsid, so it is nucleocapsid.

▪ Viruses containing envelope-antigenic in nature.

▪ Within the envelope we have an embedded glycoproteins or spikes and the

glycoproteins or the spikes for the envelope viruses are the outermost part of

the virus and they are antigenic in nature.

▪ Viruses are obligate intracellular parasite.

▪ Viruses cannot replicate on surfaces and they are obligate intracellular

parasites they should exist inside the cell in order to replicate their genome and

produce new virions.

▪ They do not have a metabolic machinery of their own-use host enzymes

(RNA or DNA)?

▪ Here we need to differentiate between RNA and DNA viruses because RNA

and DNA viruses dependency on the a host cell varies so some viruses bring

their own enzymes and others use the host enzymes just go back and review

it.

Virology – 7

Lecture 22

Date : 19/1/2021

الأسود: كلام الدكتور ✓

السلايدالأزرق: ✓

الأخضر: شرح أو توضيح خارجي ✓


▪ Certain viruses multiply in the cytoplasm, but others do in the nucleus.

▪ we gave the general rule that all DNA virus is replicating the nucleus except for

and all RNA viruses replicate in the cytoplasm except for and by this time you

should know what are the exceptions of this rule.

▪ Most multiplication take place before diagnosis is made.

▪ Here we're talking especially about the acute infections, in acute infections the

multiplication of the virus starts even before the appearance of the symptoms.

▪ Many antiviral drugs are Purine (A & G) or Pyrimidine (C & T) analogs.

▪ So for the antiviral drugs we have antiviral drugs which are purine or pyrimidine

analogues, and we mean by purine analogues being mimicking the A and G

bases or pyrimidine analogues mimicking the C and T analogues, and taking

place of the these spaces in the growing chain or in the newly produced

genome, and once they are inserted in the newly produced genome of the

virus they are going to prevent further elongation of the viral genome, and they

are going to stop the genome replication.

▪ Many antiviral drugs are Prodrugs They must be phosphorylated by viral

or cellular enzymes in order to become active.

▪ Prodrugs : that these drugs in their in this form they are not active drugs.

▪ So the phosphorylation is by viral or cellular enzyme, which do you think is

better phosphorylation by the viral or the cellular enzymes?

Of course viral enzymes is better because only cells which are infected by the

virus, in these cells the virus is going to transform the prodrug into an active

form of the drug, so this is going to minimize the side effects of the drug in the

non-infected cells but if the prodrug is transformed into the active form of the

drug using the cellular enzymes, then all the cells whether infected or non-

infected are going to transform the drug into the active form of drug and this is

going to increase the side effects of the drug on the whole body.


▪ Anti-viral agents inhibits active replication, so the viral growth resumes

after drug removal.

▪ So the antiviral drugs works on only replicating viruses and it's going to inhibit

its replication, if we're talking about like latent viruses then the antiviral drugs

are not going to work on latent viruses.

▪ Current anti-viral agents do not eliminate non-replicating or latent virus.

▪ Effective host immune response remains essential for the recovery from the

viral infection, antiviral drugs on their own are one of the mechanisms by which

we can control the viral infection, but the host immune response and an

effective host immune response remains vital and really important to contain

the viral infection, and the host immune response specifically the adaptive

immune response we're talking about the humeral arm and the cellular arm of

the adaptive immune response is really important to contain the virus and the

antiviral drugs come to help and aid in this role.

▪ Effective host immune response remains essential for the recovery from

the viral infection.

▪ Clinical efficacy depends on achieving inhibitory concentration at the site

of infection within the infected cells.

▪ That's in a way similar to what we see with antibacterial drugs, so the

antibacterial drug need to be in an effective and high concentration to inhibit

bacterial replication, it's the same here for viruses, the antiviral drug

concentration in the target cells or within the infected cells should be inhibitory

concentration in order to inhibit the viruses.

▪ Otherwise if it's a sub optimal concentration the viruses might develop adaptive

mutations, and that's one of the mechanisms by which viruses might develop

resistance against an antiviral drug.

❖ Stages of viral replication :

▪ Scientific Team

▪ Cell entry :

-Attachment

-Penetration


▪ Uncoating

▪ Transcription of viral genome

▪ Translation

▪ Assembly of virion components

▪ Release

▪ So viruses start by attachment to receptors on target cell and after that they

enter the cell by a penetration step, where penetration can occur via either

receptor receptor-mediated endocytosis or via fusion. Also we have the

uncoating step followed by the synthetic step where there is transcription of the

viral genome or genome replication and translation or synthesis and production

of a new virus protein, after the genome and the protein are being made and

ready then assembly of the these components occur to produce a new vireons,

and after that there is the release and maturation steps and the maturation

might occur before release or after release it's just a matter of time so that the

viral proteins take their final shape and become a functional.

▪ This diagram shows so this diagram shows the different steps of the viral

replication, here we have the viral absorption and we can see that we have two

drugs in phobia or fusion which acts against HIV virus, and we have the

maraviroc which is ccr5 receptor antagonist and (i think you can remember that

ccr5 is one of the core receptors for the HIV entry so both of those drugs act on

the HIV virus)

▪ After that we have the

uncoating step and the

uncoating step we have

two drugs amantidina

rimantidine which inhibit

the uncoating step in

influenza A only.

(we have influenza

A,B,C.. usually we talk

about influenzae A and

influenza B, influenza C is

not that problematic and it


is associated if it cause infection very mild infection unnoticed infection so we

usually talk about the influenza A and influenza B). Most commonly influenza A

is the circulating around so the amantidine romantidine work on the uncoating

step of influenza A.

▪ Also we have early protein synthesis which is blocked by an a drug called

fomivirsen, which affects cytomegalovirus a member of the herbesville eda

family.

▪ Also we have most of the antiviral drugs inhibited nucleic acid synthesis and

we have a purine, pyrimidine analogues, reverse transcriptase, inhibitors.

▪ Also we have late protein synthesis and processing such as protease inhibitors

and methyl zone in the variola.

▪ Also we have packaging and assembly we have the drug refampin or

fambicine.

▪ Also we have the drug which can act on the viral release step we're talking

here about neuraminidase inhibitors, which act on both influenza A and

influenza B at the same time.

When we talk about the anti-viral drugs also for also drugs for the respiratory viral

infections.

❖ Anti-herpes virus agents (All these drugs act on the herbis viridi)

▪ Acyclovir / Valacyclovir

▪ Famciclovir / Penciclovir

▪ What is the difference between the acyclovir and the valacyclovir, the

Famciclovir and Penciclovir?

Acyclovir and famciclovir require phosphorylation, and after being

phosphorylated by the viral enzymes they are going to be transformed to

valacyclovir or penciclovir.

So the difference between acyclovir and valacyclovir that Valacyclovir has

better bioavailability, penciclovir the same. When they have better

bioavailability that mean if we of the if we need like 20 microgram to be at

inhibitory concentration for certain herbis infection, then we need less initial

dosage of the valacyclovir let's say 10 5 because it has better bioavailability.

▪ Ganciclovir / Cidofovir

▪ Foscarnet

▪ Trifluridine / Idoxuridine / Vidarabine


❖ Acyclovir & related compounds:

▪ Valacyclovir is a prodrug of Acyclovir with better bioavailability.

▪ So it's a prodrug of acyclovir, valacyclovir is phosphorylated not the other way

around as i said in the previous slide, so valacyclovir is a prodrug which needs

to be phosphorylated then it becomes acyclovir like but with better

bioavailability, as we said the initial dose is going to be less in valacyclovir

compared to acyclovir.

▪ Famciclovir is hydrolyzed to Penciclovir and has greatest bioavailability.

▪ Penciclovir is used only topically whereas Famciclovir can be

administered orally.

❖ Pharmacology of acyclovir and related compounds

▪ Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are

guanine nucleoside analogs.

▪ So they resemble guanine, as we said when it resembles guanine then it's

going to be inserted and inserted in the growing genome of the virus, and once

inserted instead of the g then it's going to prevent any further elongation of the

growing genome or nucleic material of the virus, and it's going to stop virus

replication and genome production.

❖ Mechanism of action of Acyclovir and related compounds :

▪ All drugs are phosphorylated by a viral thymidine-kinase , then

metabolized by host cell kinases to nucleotide analogs.

▪ It is a good thing because only viral infected cells the prodrug is going to be

converted to the active form of the drug, and it's going to act only on the cells

which are infected by the virus and spare the non-infected cells, and this is

going to be associated with less side effects, then metabolized by the host cell

kinases to nucleotide analogues.

▪ The analog inhibits viral DNA polymerase

▪ Incorporation of acyclovir triphosphate into the growing viral DNA chain

▪ Only actively replicating viruses are inhibited


▪ This is to clarify what we're talking

about, so this is acyclovir and this

is the drug which is activated by

the viral kinase to give

acycloguanosine monophosphate

which is further activated by the

host cell kinases to give

acycloguanosine triphosphate ,this

acycloguanosine triphosphate is

going to be inserted instead in

instead of the G in the viral new

replicating viral genome and once

inserted here it's going to prevent

any further addition of bases here

and it's going to stop the

replication of the genome of the

virus.

▪ I usually resemble that like a person who has two hands, so if we're talking

about these bases (first 2 base on the left) then this base is going to have one

hand here and one hand here but this drug is going to have one hand here in

order to be inserted here but there is no hand to support any addition of other

nucleotides on this side, and it's going to the growing chain of the DNA of the

virus is going to stop here.

▪ Acyclovir is thus selectively activated in cells infected with herpes virus.

▪ Uninfected cells do not phosphorylate acyclovir.

▪ So it's going to target only the cells which are infected by the virus and spur the

non-infected cells.

❖ Antiviral spectrum :

▪ Acyclovir: HSV-1,HSV-2,VZV,Shingles.

▪ Herpes Simplex virus one usually infects above the waste and usually it is a

circumoral, Herpes Simplex virus 2 has to do with a genital infections, genitalia

it's a sexually transmitted disease.


▪ We have varicella zoster virus which causes chickenpox in children, and then

the virus goes and lie dormant, it's a latent virus it goes lie dormant in the

dorsal nerve ganglia to be activated once again after years or even decades,

and the trigger for activation of these dormant or latent viruses are old age

suppression of immunity, exposure to sunlight, exposure to UV light, infections,

all these are factors which help in the reactivation of the varicella zoster virus

and then it becomes as shingles.

▪ Usually we should we see shingles in persons aged 50s or even 60s are more

common so that's when the immune system is not as effective as before, and

this might lead to a reactivation of the latent viruses.

▪ Ganciclovir / Cidofovir : CMV

▪ Famciclovir : Herpes genitalis and shingles

▪ Foscarnet : HSV,VZV,CMV,HIV

▪ Penciclovir : Herpes labialis (which is caused by herbicides virus one)

▪ Trifluridine : Herpetic keratoconjunctivitis (which is an infection of the

cornea and the conjunctiva of the ai which is caused by Herpes simplex

virus)

❖ Pharmacokinetics of Acyclovir :

▪ Oral bioavailability ~ 20-30%

▪ When the oral bioavailability is higher then this drug is given via the oral route

once the oral bioavailability drops down to single figures maybe it's better to

look for other routes of administration.

▪ Distribution in all body tissues including CNS

▪ Renal excretion: > 80%

▪ Half lives: 2-5 hours

▪ Administration: Topical, Oral, IV

▪ Renal excretion half-lives i don't ask you to remember all these things because

you should know them in pharmacology and you might be asked about them

but here in microbiology i do not want you to focus on those things, but let's go

back to administration so if we have topical ,we have oral and we have IV in

which cases can we give the topical? and which case can we give the oral ?

and which case can we give the IV?


▪ So here we're talking about the Herpes Simplex virus infection, topical as we

said there is the cold sore or the fever blister which is circumaural, where it

starts with legion which becomes filled with fluid and then it postulates become

yellow or whitish yellowish color, cut in color due to the presence of pus there,

so in this case we can use the topical ointment to treat it.

▪ At the same time we can also use the oral also in the case of shingles where

we have reactivation of the virus, then the we can use the topical on the legion

which mimics the herbicides virus legions which are pulse, but they are very

painful and at the same time we can give the oral medication in order to

support or drop significantly the virus replication, and at the same time in the

case of the shingles we need to give strong painkiller because the pain in case

of shingle is very severe.

▪ As we said previously if the a pregnant woman is screened and she has

Herpes Simplex virus, it is contraindicated to deliver vaginally she should be

delivered by a cesarean section, because if the baby was delivered vaginally

then he has a high chance of becoming infected with Herpes Simplex virus,

and as a result this is going to lead to infection of the cns, brain of the baby,

and it's going to lead to liquefication of the brain of the baby and death is

expected in 90-100% of the cases, also in certain cases the herbis might cause

meningitis encephalitis, if we suspect any patient to have hepatic encephalitis

or meningitis then the drug should be given IV.

❖ Adverse effects of Acyclovir / Ganciclovir

▪ Nausea, vomiting and diarrhea

▪ Nephrotoxicity - crystalluria, haematuria,renal insufficiency

▪ Myelosuppression - Neutropenia and thrombocytopenia Ganciclovir

❖ Therapeutic uses :

▪ Acyclovir is the drug of choice for :

-HSV Genital infections (caused by Herpes Simplex virus 2)

-HSV encephalitis

-HSV infections in immunocompromised patient


▪ Ganciclovir is the drug of choice for :

- CMV retinitis in immunocompromised patient

- Prevention of CMV disease in transplant patients

▪ Usually cytomegalovirus does not infect immunocompetent persons it rather

infects immunocompromised patients with aids, or those who are on

immunosuppressive medications, and in the in this case the ganciclovir is the

drug of choice, as we said in acyclovir it is activated by the viral enzyme

thymidine kinase, in cytomegalovirus there is another viral enzyme which is

responsible for activating the ganciclovir or transforming the ganciclovir into the

active form of the drug.

(This is your homework to do what is the name of the enzyme which activates

ganciclovir)

❖ Cidofovir :

▪ Scientific Team

▪ It is approved for the treatment of CMV retinitis in immunocompromised

patients and Adenovirus infections. (it's not specific for adenovirus but it

was shown to be effective in certain circumstances with adenovirus

infection)

▪ It is a nucleotide analog of cytosine no phosphorylation required.

▪ So acyclovir and the others were guanine analogues here we have the

cytophore is a cytosine analog so it resembles the c but this one does not

require phosphorylation, so it is in the active form of the drug once given.

▪ When we say that this is a nucleotide analog of cytosine and no

phosphorylation is required, then the first thing that should come to mind is that

this might be associated with more side effects compared to the acyclovir and

other related drugs, because it's going to act on infected and non-infected cells

at the same time.

▪ It inhibits viral DNA synthesis.

▪ Available for IV, Intravitreal inj, topical.

▪ Nephrotoxicity is a major disadvantage.


❖ PHARMACOLOGY OF VIDARABINE

Vidarabine is a nucleoside analog. (adenosine)

▪ Antiviral spectrum of Vidarabine :

HSV-1,HSV-2 and VZV. Its use is limited to HSV keratitis only.

❖ Vidarabine

▪ The drug is converted to its triphosphate analog which inhibits viral DNA

polymerase.

▪ Oral bioavailability ~ 2%

▪ Oral body availability is low so it's not given orally it is given as an ophthalmic

ointment.

▪ Administration: Ophthalmic ointment

▪ Used in HSV keratoconjunctivitis in immunocompromised patient.

▪ Anemia and SIADH are adverse effects.

❖ PHARMACOLOGY OF TRIFLURIDINE

▪ Trifluridine is a Pyrimidine nucleoside analogs inhibits viral DNA

synthesis.

❖ Antiviral spectrum Trifluridine :

▪ HSV-1, HSV-2 and VZV.

▪ Use is limited to Topical Ocular HSV Keratitis

❖ PHARMACOLOGY OF FOSCARNET

▪ Foscarnet is an inorganic pyrophosphate analog.

▪ It directly inhibits viral DNA and RNA polymerase and viral reverse

transcriptase (it does not require phosphorylation for antiviral activity).

▪ So like cytophobia this does not require phosphorylation it's in the active form

of the drug, and it it inhibits DNA and RNA polymerase and reverse

transcriptase as well.

❖ Foscarnet

▪ HSV-1 , HSV-2 , VZV, CMV and HIV.



▪ Distribution to all tissues including CNS

▪ Administration: IV

❖ Therapeutic uses of Foscarnet

▪ It is an alternative drug for :

-HSV infections (acyclovir resistant / immunocompromised patient).

-CMV retinitis ( ganciclovir resistant / immunocompromised patient).

The fuscarnet was the last drug that we talked about for treatment of herbicide

virus and infections .

❖ Respiratory viral infections

▪ Scientific Team

▪ Influenza :

-Amantadine / Rimantadine

▪ Amantadine and rimantadine as we've mentioned on the figure shown at the

beginning acts on the uncoating step and it is only effective for influenza A.

Amantadine and rimantadine are neuraminidase inhibitors and once given they

prevent the release of the influenza virus from the infected cell, and then they

drop the amount of the infectious virus which are produced from that cell, so

they belong to the neuraminidase inhibitors resistance to amantadine

rimantadine is very high it might reach 90-95 percent.

-Oseltamivir / Zanamavir (Neuraminidase inhibitors)

▪ Oseltamivir and Zanamavir are better given and the Oseltamivir and Zanamavir

are more widely used nowadays for influenza virus infection.

▪ RSV bronchiolitis :

- Ribavirin

▪ as we said causes bronchiolitis and bronchopneumonia in infants and small

children we're talking mostly about one year to two years of age and it can in

this case we can use the ribba vereen to treat those children.


❖ Amantadine and Rimantadine : Influenza

▪ Prevention & Treatment of influenza A.

▪ So if someone has been diagnosed with influenza virus and diagnosis is

usually clinical with influenza infection, patients usually present with fever,

rhinorrhea, coughing, sneezing, general fatigue, arthralgia and myalgia, so if

we diagnose the the patient has been infected influenza virus, we might use

the amentidine or rimentidine, and it can be used in prevention we're going to

come to that later on.

▪ Inhibition of viral uncoating by inhibiting the viral membrane protein

M2.

▪ Influenza A virus only.

▪ The viral membrane protein m2 is only present in an influenza A viruses it's

not present in influenza B virus, so that's why we say that amantidina

rimantidine can be used only for influenza A; because it acts on a protein which

is only present in influenza A virus it's not present in influenza B viruses, so

even if given for influenza B there is no m2 protein and it's not going to be

active against influenza B viruses.

▪ So once again it blocks the m2 protein disrupts hydro transport while encoding

in wholesale, and therefore viral rna transcription so it is used only for

influenza-A.


❖ Pharmacokinetics of Amantadine


▪ Amantadine cross extensively BBB whereas Rimantadine does not cross

extensively.

▪ Administration: Oral

▪ As we said the resistance is very high with Amantadine/Rimantadine in and it

might reach up to 90-95%.

❖ Neuraminidase inhibitors : Influenza A & B Oseltamivir / Zanamavir

▪ Influenza contains an enzyme neuraminidase which is essential for the

replication of the virus.

▪ Neuraminidase inhibitors prevent the release of new virions and their

spread from cell to cell.

▪ The neuraminidase enzyme we have if you remember when we talked about

the influenza virus we have two glycoproteins the HA and the NA, the NA is the

neuraminidase, so the HA is used for mainly for attachment to receptor and

entry of the influenza virus into the target cell.

The NA has multiple functions, one of them is to attachment with the virus

before release, and after that it cleaves the bond between the virus and the NA

and set the virus free, if we use the neuraminidase inhibitor then it's going to

prevent this cleavage of the binding between the virus and the NA, and it's

going to prevent the release of the new virion, and it's going to minimize the

number of infected cells nearby.

❖ Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir

▪ Scientific Team

▪ These are effective against both types of influenza A and B.

▪ Do not interfere with immune response to influenza A vaccine.

▪ Can be used for both prophylaxis and acute treatment.

▪ So let's get to the prophylaxis and acute treatment, in the case of acute

treatment as we said the patient might be symptomatic with influenza virus

infection and we mentioned other symptoms that patient might come with, so in

this case we can use either the amount of derivation or Oseltamivir /

Zanamavir.


▪ But in case of prophylaxis we're doing it by giving it prophylactically

(prophylaxis when we say we want to give a drug as a prophylaxis then we

want to give the drug before the patients get infected by the virus as a

precautionary measure) what are the cases in which we can give these drugs

antiviral drugs or the influenza drugs prophylactically?

In the case of pandemic, if we have a pandemic and the virus is spreading

quickly then we can give the virus at the under the virus prophylactically, also

in case there is in the household we have like five four six living in the same

house and three or four of them got infected with influenza virus so most

probably the other two are going to become infected so we can give them

prophylactically the Oseltamivir / Zanamavir. Also in the case of

immunocompromised patients who are immunocompromised and they get into

contact with patients who are infected with the influenza virus then we can give

them a prophetically.

▪ Oseltamivir is orally administered.

▪ Zanamavir is given intranasal.

▪ Risk of bronchospasm with zanamivir.(so this is one of the side effects of

the zanamivir)

❖ PHARMACOLOGY OF RIBAVIRIN

▪ Ribavirin is a guanosine analog.

▪ Requires phosphorylation to mono --, di and triphosphate

▪ Triphosphate Inhibits RNA polymerase and depletes cellular stores of

guanine (inhibit IMDH)

▪ Decrease synthesis of mRNA 5 ’ cap (interfere with guanylation and

methylation of nucleic acid base)

▪ so it's a guanosine analogue requires phosphorylation to monodyne

triphosphate, triphosphate inhibits RNA polymerase and the bleed cellular

stores of guanine, then a decreased synthesis of messenger RNA which would

interfere with the granulation and methylation of a nucleic acid basis so this is

the mechanism for action of the ribovirine, the antiviral drug ribavirian can be

given for RNA viruses including influenza, para-influenza, respiratory sensitive

viruses, the drug of choice in the case of respiratory syncytial virus, it can be

given for lassovirus infection, can be given for hepatitis C virus infection as


well, in addition to pigelated interferon in the case of hepatitis C, proved to be

somehow effective.

Antiviral spectrum :

RNA viruses are susceptible, including influenza, parainfluenza viruses, RSV,

Lassa virus.

❖ Ribavirin : RSV

▪ Distribution in all body tissues, except CNS.

▪ Administration : Oral, IV, Inhalational in RSV.

▪ Anemia and jaundice are adverse effects.

▪ Not advised in pregnancy.

❖ Therapeutic uses Ribavirin

Ribavirin is the drug of choice for:

▪ RSV bronchiolitis and pneumonia in hospitalized children (given by

aerosol) or sometimes they are given in what they call the oxygen tent or

the tent so the the drug is irrusalized within the tent and the then the

children are going to breathe it and take an end take it and into the lungs.

▪ Lassa fever

Ribavirin is the drug of choice for:

▪ Influenza, parainfluenza , measles virus infection in immunocompromised

patients.

▪ As we said in addition to pigelated interferon can be used for hepatitis C virus

infections as well.

❖ Hepatic Viral infections :

▪ Interferons

▪ Lamivudine - cytosine analog HBV

▪ Entecavir - guanosine analog HBV lamivudine resistance strains

▪ Ribavirin - Hepatitis C (with interferons)


▪ Sofosbuvir - nucleotide analog used in combination with other drugs

(Ribavirin and Interferon) for the treatment of hepatitis C virus (HCV)

infection. Course of 12 weeks cost 84,000$.

▪ When we say hepatitis viral infection we have hepatitis A,B,C,D,E,F,G, we

have that much after hepatitis viral infections, but most viral infections are

acute infections apart from hepatitis B and hepatitis C which are chronic

hepatitis viral infections, and in this case we can use interferons which

suppress the immunity, we can use lamivudine which is a cytosine analog can

be used for hepatitis B, we can use Entecavir which is a guanosine analog for

hepatitis B, and for the hepatitis B where the strains are lamivudine resistance

so we can use either lamivudine in case of resistance to lamivudine, we can

use Entecavir for hepatitis c we can use the Ribavirin with Pegylated

interferons, and there is a newly approved drug by the FDA (i think in 2013 or

2014) which is the Sofosbuvir, which is a nucleotide analog used in

combination with other drugs either ribavirin and interferon initially once the

surface Sofosbuvir was approved it was used with riverine and Pegylated

interferon for the treatment of hepatitis C virus infection.

▪ Nowadays Sofosbuvir is not used with interferon anymore or Ribavirin, there

are other combinations that has proved to be more efficient and once the

surface revere was approved, the course consisted of 12 week treatment and

during the 12 weeks the patient takes one per day, so we're talking about 84

bells for the whole treatment period, and the single bell was priced at 1,000 US

dollars so it is one of the expensive drugs, but it is associated with complete

cure and recovery from hepatitis C virus infection.

❖ Hepatitis C treatment

▪ 1986 - Non-A, non-B hepatitis was identified as hepatitis C.

▪ 1990s - Interferon. Ribavirin was added to interferon therapy. (Ribavirin

was added to interferon and it was effective at around 50 percent)

▪ 2001 - Pegylated interferon was approved. Pegylated interferon

increased its half-life leading to reduced injection frequency and at the

same time increased the sustained virological response. (that would lead

to giving the Pegylated interfere interferon as a single shot for one week

or 10 days instead of giving it daily in the case of the classic interferon

with the Ribavirin)


▪ 2011 - The first direct acting antiviral or NS-3/4A (protease inhibitor)

boceprevir was approved. Thereafter other inhibitors in this class

telaprevir, simeprevir, asunaprevir, paritaprevir and grazoprevir were

approved.

▪ 2013 - The first NS5B polymerase inhibitor sofosbuvir approved.

Dasabuvir was approved in 2014. (Dasabuvir approved as another ns5b

inhibitor of hepatitis c)

▪ 2014 - The first NS5A inhibitor ledipasvir was approved. Four other NS5A

inhibitors of this class-daclatasvir, ombitasvir , elbasvir and velpatasvir

have been subsequently approved.

▪ But nowadays they found that NS5A and NS5B combination has shown a

greater results with cure rate ranging from 30-100% depending on the

genotype of the hepatitis C, so we have genotypes one to six and depending

on the genotypes the cure rate was seen from 30-100% in depending on the

genotype of the hepatitis C.


▪ Now we're going to talk

about the last group of

the antiviral drugs which

are used to treat the

retroviridae, and one of

the members of the

retroviridae is the HIV,

the HIV in this picture

we can see we have the

glycoprotein or the spike

which is composed of

120 which is the outer

part of the glycoprotein, and we have the transmembrane or the envelop

embedded part of it is the gb41 here.

▪ Then we have the icosahedron capsid, we have two copies of the positive

sense singularly stranded RNA (HIV is unique that it's a diploid has two copies

of the positive sense single-stranded RNA), also it has an enzyme reverse

transcriptase, it has the matrix protein, and it has the integrase enzyme, it has

the protease enzyme.

By now you should know the replication cycle of the HIV if not please go back

and remind yourself of the replication cycle of the HIV, it's really important and i

think question might be in the exam regarding the replication cycle of HIV.

▪ So why are we about the structure of HIV here? because for the HIV there are

multiple drugs that affect or that block different steps of the viral replication,

and affect different enzymes, so there are inhibitors of the integrase enzyme

there are inhibitors of protease enzyme there are inhibitors of the fusion and

penetration of the virus into the target cell, and there are inhibitors of the

reverse transcriptase enzyme as well.


Antiretroviral Drugs

▪ Usually when we talk about antiretroviral drugs we talk about the heart which is

the highly active anti-retroviral therapy, and the heart usually includes a

combination of three medications, as we said in the HIV we have drugs that

target multiple steps of the viral application, so in this cocktail that we use in

the heart usually we use drugs that act on the entry step which are entry

inhibitors, protease inhibitors, integrase inhibitors and reverse transcriptase

inhibitors.

▪ So combination of these three drugs are used to reduce the amount of newly

produced viruses and to decrease the viral load.

❖ HAART - Highly active antiretroviral therapy

▪ Includes at least three medications – “cocltails”

▪ These medications work in different ways to reduce the viral load

❖ Fusion inhibitors

▪ Inhibit viral fusion, preventing viral replication

▪ Newest class of antiretroviral drugs

▪ Example: enfuvirtide (Fuzeon)

▪ Used in combination with other drugs active against HIV

▪ Side effects:

peripheral neuropathy, insomnia, depression, cough, dyspnoea,

anorexia, arthralgia

❖ Entry inhibitor

▪ Inhibit viral entry into macrophages a T cells.

▪ CCR5 receptor antagonist (its name is Maraviroc)

▪ FDA approved in 2007

▪ Maraviroc (Selzentry, or Celsentri outside the U.S)

▪ Used in combination with other drugs active against HIV

▪ HIV can also use other coreceptors, such as CXCR4, an HIV tropism test

such as a trofile assay must be performed to determine if the drug will be

effective.


▪ Safety issues regarding blocking CCR5, a receptor whose function in the

healthy individual is not fully understood.

▪ Since it acts on the CCR5 receptor antagonist which is a receptor present on

our cells and it's not specific to the virus, so blocking the receptors on our cells

the CCR5 receptor function in our body is not really well known and studied, so

blocking the receptor could be associated with multiple side effects, studies are

still underway to see the efficacy and the safety of the drug.

❖ Ibalizumab :

A monoclonal antibody that binds to domain 2 of CD4 and interferes with

post attachment steps required for the entry of HIV 1 virus particles into host

cells and prevents cell-cell fusion.

❖ Reverse transcriptase inhibitors (RTIs)

▪ which is responsible for the replication of the genome of the HIV virus

▪ Block activity of the enzyme reverse transcriptase, preventing production

of new viral DNA

❖ Reverse transcriptase inhibitors (RTIs)

▪ Nucleoside RTIs (NRTIs): Azidothymidine (AZT), Didanosine (ddI),

Stavudine (D4T), Lamivudine (3TC).

▪ Nonnucleoside RTIs (NNRTIs): Nevirapine, delavirdine,efavirenz.

▪ Nucleotide RTIs (NTRTIs):Tenofovir, Adefovir.

▪ Nucleoside reverse transcriptase translocation inhibitor (NRTTIs) :

Islatravir (Investigational drug). (still under investigation has not been

approved yet)

❖ Nucleoside RTIs (NRTIs): (once phosphorylated they become the

nucleotide reverse transcriptase inhibitors)

Azidothymidine (AZT), Didanosine (ddI), Stavudine (D4T), Lamivudine 3TC)

▪ Do not worry too much about the names, there are more members of each one

group of the reverse transcriptase inhibitors, if i bring any question in the exam

i'm gonna tell you if i bring a single name like that let's say Lamivudine i'm

gonna mention that this is a reverse transcriptase inhibitor, so do not worry too

much about memorizing these names.


▪ Requires phosphorylation by host cellular enzymes (kinases) to their

active triphosphate form.

▪ Selective therapeutic effect: HIV RT is more sensitive to AZT than is host

cell DNA polymerase.

▪ As we said since it is activated by the host cell enzymes or kinases, then it's

going to inhibit both the cellular replication and the viral replication, but here we

need to mention something very important :

If during the investigational phase they found that a certain drug has the ability

to inhibit the whole cellular replication or the host cellular replication is inhibited

at the same level and same degree as the viral replication, then this drug is not

going to hit the shelves for sure; because it's not going to be approved

because it's going to be associated with great side effects, but they found that

here for the for the azidothymidine it is more sensitive to the reverse

transcriptase of the HIV, so if it inhibits the cellular DNA let's say by 1-2% then

it is going to inhibit the reverse transcriptase by 30-40%, so it has more affinity

to the reverse transcriptase of the virus than to the DNA polymerase of the cell.

❖ Nonnucleoside RTIs (NNRTIs): Nevirapine , delavirdine , efavirenz

▪ Scientific Team

▪ Active against HIV 1.

▪ Do not require cellular enzymes to be Phosphorylated.

▪ Do not inhibit human DNA polymerase.

▪ Relatively safe: noncytotoxic.

▪ Highly prone to drug resistance.

▪ Used in combination with other drugs active against HIV0

❖ Integrase enzyme inhibitors :

A class of antiretroviral drug designed to block the action of integrase , a

viral enzyme that inserts the viral genome into the DNA of the host cell.

▪ integrase enzyme : is the enzyme that makes sticky end in the viral genome,

and then incorporate the viral genome into the host genome.

▪ Raltegravir --- 2007

▪ Elvitegravir --- 2012

▪ Dolutegravir --- 2013

▪ Bictegravir --- 2018


▪ MK 2048 (which is an investigational drug) --- duration of action up to

four times longer than raltegravir (it has not been approved yet by the

FDA style under investigation)

▪ Portmanteau inhibitors : inhibit both reverse transcriptase (RT) and

integrase (IN) at the same time.

❖ Protease inhibitors (PIs)

▪ As you remember when we talked about translation of the HIV genome into

protein, it usually is translated into a long chain of polyprotein attached to each

other, and then protease enzyme comes and cleaves this long chain into

individual proteins to become a functional, if we prevent this cleavage process

then via the protease inhibitors then we we're going to prevent any assembly

and production of the new virulence.

▪ Inhibit the protease retroviral enzyme, preventing viral replication.

▪ Inhibition of this enzyme blocks viral assembly and release.

▪ Examples:

-amprenavir (Agenerase)

-nelfinavir (Viracept)

-saquinavir (Invirase)

A patient also should be monitored closely for hepatotoxicity and as with other

drugs it's usually given in combination with other classes of the antiretrovirals.

-indinavir (Crixivan)

-ritonavir (Norvir)

▪ Hepatotoxic

▪ Used in combination with other drugs active against HIV.

▪ Combinations of multiple antiretroviral medications are common.

▪ The use of a single drug in the case of HIV is contraindicated, because it's

going to lead to resistance very shortly, so medications should be given in


combination and the heart is needs to be given in a cocktail of three medication

which act on different steps of the viral replication.

▪ Adverse effects vary with each drug and may be severe-monitor for dose

limiting toxicities. So the patient needs to be monitored for those limiting

toxicity, and if we notice any toxicities there should be adjustment of the

dose lowering the dose or even switching to another drug.

▪ Monitor for signs of opportunistic diseases.

▪ In case when the patient is on the antiviral drugs we need to monitor the CD4

count ,so if the CD4 count goes higher then there is a good response to the

antiviral drugs, if the CD4 count goes down below 200 we said that this patient

is labeled as an aids patient and he's going to be prone to opportunistic

disease, so during the time of treatment we should monitor for signs of

opportunistic diseases.

That's all for the anti-retroviral drugs

❖ Interferons

▪ Interferons : (IFNs) are natural proteins produced by the cells of the

immune systems in response to challenges by foreign agents such as

viruses, bacteria, parasites and tumor cells.

And we mentioned that in a previous lecture and we showed the mechanism by

which the interferons will warn the nearby cells that there is an infecting virus,

and how they activate the gene and produce the interferon.

▪ Antiviral, immune modulating and anti-proliferative actions.

▪ these interferons are external interferons, not the ones that are synthesized, so

they are synthesized those are manufactured interferons, they used as an

antiviral, they are used as immune modulating and anti-proliferative actions

▪ Three classes of interferons - α , β, γ.

- α and β interferons are produced by all the cells in response to viral infections.

- γ interferons are produced only by T lymphocyte and NK cells in response to

cytokines - immune regulating effects.

- γ has less anti-viral activity compared to α and β interferons.


❖ Mechanism of action of Interferons

▪ Induction of the following enzymes:

1) a protein kinase which inhibits protein synthesis.

2) an oligo-adenylate synthase which leads to degradation of viral mRNA.

3) a phosphodiesterase which inhibit t RNA The action of these enzymes leads to

an inhibition of translation.

❖ Antiviral spectrum : Interferon α

▪ Includes HBV, HCV (Pegylated interferon) and HPV.

▪ The new Pegylated interferon we said that the NS5 A and B inhibitors are used

instead of the Pegylated interferon, even Pegylated interferon is associated

with multiple side effects, so nowadays they refrain from using the interferon

or even Pegylated interferon for a better quality of life for the patients, and it

can be used also for the human papillomavirus infection.

▪ Addition of polyethylene glycol to the interferon, through a process

known as pegylation , enhances the half-life of the interferon when

compared to its native form.

▪ Anti proliferative actions may inhibit the growth of certain cancers - like

Kaposi sarcoma (Kaposi sarcoma when we talk about HIV) and hairy cell

leukemia.

▪ Kaposi sarcoma is a legion which is seen in the aids patients, and when they

started the Kaposi sarcoma they isolated the human herpes virus eight from

100% of the Kaposi sarcoma legion, so Kaposi sarcoma is could caused by an

infection or reactivation of the human herpes virus eight during the aids in the

aids patients.

❖ Pharmacokinetics : Interferons

▪ Oral bioavailability: < 1%.

▪ Administered Intralesionally, S.C, and I.V.

▪ Distribution in all body tissues, except CNS and eye.

▪ Half lives: 1-4 hours.


❖ Adverse effects of Interferons

▪ Acute flu-like syndrome (fever, headache)

▪ Bone marrow suppression (granulocytopenia, thrombocytopenia)

▪ Neurotoxicity (confusion, seizures)

▪ Cardiotoxicity - arrhythmia

▪ Impairment of fertility

❖ Therapeutic uses Interferons

▪ Chronic hepatitis B and C (complete disappearance is seen in 30%).

▪ HZV infection in cancer patients (to prevent the dissemination of the

infection).

▪ CMV infections in renal transplant patients.

▪ Condylomata acuminata (given by intralesional injection). Complete

clearance is seen ~ 50%.

▪ Hairy cell leukemia (in combination with zidovudine)

▪ AIDS related Kaposi s sarcoma


Quick Summary..

❤️

Virus Diseases Drug(s) of choice Alternative

drugs

FLU A Influenza Amantadine Rimantadine

RSV Pneumonia, bronchiolitis Ribavirin (aerosol)

HSV Genital herpes Acyclovir Foscarnet

Keratitis Conjunctivitis Trifluridine Idoxuridine Vidarabine

Encephalitis Acyclovir

Neonatal HSV infection Acyclovir Vidarabine

Herpes infections in immuno-compromised host

Acyclovir Foscarnet

VZV In normal host No therapy

In immunocompromised host, or during pregnancy

Acyclovir Foscarnet

CMV Retinitis Ganciclovir Foscarnet

HIV AIDS HIV antibody positive with CD4

count < 500/mm3

Zidovudine ± protease inhibitors

Didanosine, Stavudine

HBV

HCV

Hepatitis B, C Interferons Ribavirin Sofosbuvir Ledipasvir

lecture ٢٢ - humsc

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