Antiviral drugs

PREPARED BY: JEGAN NADAR
ANTI-VIRAL DRUGS

ANTI-VIRAL DRUGS
● Viruses are obligate intracellular parasites.
● They lack both a cell wall and a cell membrane, and they do not carry out metabolic
processes
● Viruses use much of the host’s metabolic machinery, and few drugs are selective enough
to prevent viral replication without injury to the infected host cells.
● 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 stage of viral infection, administration of drugs that block viral replication has
limited effectiveness

VIRUS
REPLICATION
1.Binding
2.Fusion
3.Reverse Transcription
4.Integration
5.Replication
6.Assembly
7.Budding

BINDING
● Proteins, called envelope proteins,
embedded in the outer membrane of the
HIV virion bind to receptors on the surface
of target cells.
● T-cells (white blood cells) have CD4 and
CCR5 receptors to which HIV can bind.

FUSION
● Binding of the HIV envelope protein to CD4
and CCR5 allows the HIV-1 outer membrane
to fuse with the cell’s outer membrane
● HIV RNA, reverse transcriptase, integrase
and other viral proteins enter the cell.

REVERSE TRANSCRIPTION
● Once inside a CD4 cell, HIV releases and
uses reverse transcriptase (an HIV enzyme)
to convert its genetic material—HIV
RNA—into HIV DNA.
● The conversion of HIV RNA to HIV DNA
allows HIV to enter the CD4 cell nucleus and
combine with the cell’s genetic material—cell
DNA.

INTEGRATION
● The viral DNA enters the nucleus of the host and
becomes integrated into the host’s DNA.
● An enzyme called integrase is key in this process.
● Once the viral DNA has integrated into the cell’s
DNA, the cell is infected for the remainder of its life.
● The integrated viral DNA is now referred to as a
provirus.

REPLICATION
● The provirus DNA serves as a template for the creation
of new viral RNA via a process known as transcription
● The newly formed viral RNA moves out of the infected
cell’s nucleus.
● The viral RNA carries code for the synthesis of viral
proteins and enzymes.
● The code is translated into long chains of amino-acids,
known as a polypeptide chains, which fold to form the
protein and enzyme components of new virus particles.

ASSEMBLY
Components that are required to build new
virus particles, namely viral proteins,
enzymes and genetic material (viral RNA)
move to the cell’s outer membrane where
they accumulate and assemble in the form of
a bud.
A variety of host cell proteins are recruited to
assist in virus assembly.

BUDDING
Host-cell proteins cut the virus bud from
the cell’s outer membrane, thereby
releasing a new virus particle

ANTI-HERPES VIRUS DRUGS
● These are drugs active against the Herpes group of DNA viruses which include
◆ Herpes simplex virus-1 (HSV-1),
◆ Herpes simplex virus-2 (HSV2),
◆ Varicella-Zoster virus (VZV),
◆ Epstein-Barr virus (EBV),
◆ Cytomegalovirus (CMV).

Idoxuridine & Trifluridine
● Progress in antiviral chemotherapy began in the early 1950s, when the search for anticancer drugs
generated several new compounds capable of inhibiting viral DNA synthesis.
● The two first-generation antiviral agents, 5-iododeoxyuridine and
trifluorothymidine, had poor specificity (ie, they inhibited host cell DNA as well as
viral DNA) that rendered them too toxic for systemic use.
● It competes with thymidine, gets incorporated in DNA so that faulty DNA is
formed which breaks down easily.
● However, both agents are effective when used topically for the treatment of herpes
keratitis

Acyclovir
● Acyclovir is an acyclic guanosine derivative with clinical activity against
HSV-1, HSV-2, and VZV, but it is approximately 10 times more potent
against HSV-1 and HSV-2 than against VZV.
● It is the treatment of choice in HSV encephalitis.

● Acyclovir, a guanosine analog, is monophosphorylated in the cell by the
herpesvirus-encoded enzyme thymidine kinase
● Therefore, virus-infected cells are most susceptible.
● The monophosphate analog is converted to the di- and triphosphate forms
by the host cell kinases.
● Acyclovir triphosphate competes with deoxyguanosine triphosphate as a
substrate for viral DNA polymerase and is itself incorporated into the viral
DNA, causing premature DNA chain termination.
MECHANISM OF ACTION

Acyclovir
● Acyclovir is administered by intravenous (IV), oral, or topical routes.
● The drug distributes well throughout the body, including the cerebrospinal fluid
(CSF).
● Acyclovir is partially metabolized to an inactive product.
● Excretion into the urine occurs both by glomerular filtration and tubular secretion
● Acyclovir accumulates in patients with renal failure.

Acyclovir-Adverse effects
● Topical: Stinging and burning sensation after each application.
● Oral: The drug is well tolerated; headache, nausea, malaise and some CNS
effects are reported.
● Intravenous: Rashes, sweating, emesis and fall in BP occur only in few patients

Use
● Genital Herpes simplex
● Mucocutaneous H. simplex
● H. simplex encephalitis
● H. simplex (type I) keratitis
● Herpes zoster
● Chickenpox

Amantadine & Rimantadine
● Amantadine and its α-methyl derivative, rimantadine, are tricyclic amines of the
adamantane family
● They block the M2 proton ion channel of the virus particle
● Thus they inhibit the uncoating of the viral RNA within infected host cells,
● This prevents its replication.
● They are active against influenza A only

● The antiviral activity of amantadine is strain specific; influenza B is not affected.
● They are active against influenza A only.
● Moreover, H5N1 (avian influenza/bird flu) and H1N1 (swine flu) strains of
influenza A are resistant in most areas.

● Both drugs are well absorbed after oral administration.
● Amantadine distributes throughout the body and readily penetrates into the
central nervous system (CNS)
● Rimantadine does not cross the blood–brain barrier to the same extent.
● Amantadine is primarily excreted unchanged in the urine, and dosage reductions
are needed in renal dysfunction.
● Rimantadine is extensively metabolized by the liver, and both the metabolites and
the parent drug are eliminated by the kidney

Amantadine & Rimantadine-Adverse effects
● The most common adverse effects are gastrointestinal (nausea, anorexia) and
central nervous system (nervousness, difficulty in concentrating, insomnia,
light-headedness)
● More serious side effects (eg, marked behavioral changes,
delirium, hallucinations, agitation, and seizures) may be due
to alteration of dopamine neurotransmission
● These side effects are less frequent with rimantadine than with amantadine

Oseltamivir
● This newer anti-influenza virus drug is a sialic acid analogue with broad spectrum
activity.
● The neuraminidase inhibitors oseltamivir and zanamivir are effective against both
type A and type B influenza viruses covering influenza A (amantadine sensitive
as well as resistant), H5N1 (bird flu), H1N1 (swine flu) strains and influenza B.
● It is an ester prodrug that is rapidly and nearly completely hydrolysed during
absorption in intestine and by liver to the active form oseltamivir carboxylate

● Influenza viruses employ a specific neuraminidase that is inserted into the host
cell membrane for the purpose of releasing newly formed virions.
● This enzyme is essential for the virus life cycle.
● Oseltamivir and zanamivir selectively inhibit neuraminidase, thereby preventing
the release of new virions and their spread from cell to cell.

ANTI-HEPATITIS VIRUS
/NONSELECTIVE ANTIVIRAL DRUGS

ANTI-HEPATITIS VIRUS
● Several antiviral drugs are relatively virus non-selective and inhibit viruses
belonging to different classes; even cover both DNA and RNA viruses.
● While hepatitis B virus (HBV) is a DNA virus which, like retroviruses, can
integrate into host chromosomal DNA to establish permanent infection, the
hepatitis C virus (HCV) is a RNA virus, which does not integrate into
chromosomal DNA

Adefovir
● Adefovir is a monophosphate analogue of AMP which is active against HBV and some
other DNA as well as RNA viruses, but is used only for hepatitis caused by HBV.
● After entering the cell, it is phosphorylated by cellular kinases to adefovir diphosphate,
which is then incorporated into viral DNA.
● This leads to termination of chain elongation and prevents replication of HBV.
● Adefovir is administered once a day and is renally excreted via glomerular filtration and
tubular secretion
● While its plasma t1⁄2 is 7 hours, intracellular t1⁄2 of the diphosphate is upto 18 hours.

ANTI-RETROVIRUS DRUGS
● These are drugs active against human immunodeficiency virus (HIV) which is a
retrovirus.
● They are useful in prolonging and improving the quality of life and postponing
complications of acquired immunodeficiency syndrome (AIDS) or AIDS related
complex (ARC), but do not cure the infection.

Nucleoside reverse transcriptase inhibitors
(NRTIs)

Zidovudine
● Zidovudine is a thymidine analogue (azidothymidine, AZT), the prototype NRTI.
● On the template of single-stranded RNA genome of HIV, a double-stranded DNA copy
is produced by viral reverse transcriptase.
● This proviral DNA translocates to the nucleus and is integrated with chromosomal
DNA of the host cell (by viral integrase enzyme) which then starts transcribing viral
genomic RNA as well as viral mRNA.
● Under the direction of viral mRNA, viral regulatory and structural proteins are
produced in the form of a polyprotein.

● Finally, viral particles are assembled and matured after fractionation of the
polyprotein by viral protease
● Inside the cell Zidovudine is phosphorylated to Zidovudine triphosphate
● Zidovudine triphosphate selectively inhibits viral reverse transcriptase
● Zidovudine thus prevents infection of new cells by HIV, but has no effect on
proviral DNA that has already integrated into the host chromosome.
● It is effective only against retroviruses

Zidovudine
● The oral absorption of AZT is rapid, but bioavailability is ~65%.
● It is quickly cleared by hepatic glucuronidation (t½ 1 hr)
● 15–20% of the unchanged drug along with the metabolite is excreted in urine
● It crosses placenta and is found in milk.

Adverse Effects and Use
● AZT is toxic to bone marrow and can cause anemia and neutropenia
● Headaches are also common
● Nausea, anorexia, abdominal pain, insomnia and myalgia are common at the start
of therapy, but diminish later.
● Zidovudine is used in HIV infected patients only in combination with at least 2
other ARV drugs.
● It is one of the two optional NRTIs used by NACO for its first line triple drug ARV
regimen.

Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)

Nevirapine (NVP) and Efavirenz (EFV)
● These are nucleoside unrelated compounds which directly inhibit HIV reverse
transcriptase without the need for intracellular phosphorylation.
● Their locus of action on the enzyme is also different, and they are non-competitive
inhibitors.
● They are more potent than AZT on HIV-1, but do not inhibit HIV-2.
● Cross-resistance between NVP and EFV is common, but not with NRTIs or PIs

● NNRTIs are highly selective, noncompetitive inhibitors of HIV-1 RT.
● They bind to HIV RT at an allosteric hydrophobic site adjacent to the active site,
inducing a conformational change that results in enzyme inhibition.
● They do not require activation by cellular enzymes.
● These drugs have common characteristics that include cross-resistance
● The most frequently observed adverse effects are rash, fever, headache, and
elevated serum transaminases and fatal hepatotoxicity

Nevirapine
● Nevirapine is well absorbed orally.
● The lipophilic nature of nevirapine accounts for its wide tissue distribution,
including the CNS, placenta (transfers to the fetus), and breast milk.
● Nevirapine is metabolized via hydroxylation and subsequent glucuronide
conjugation.
● The metabolites are excreted in urine.
● Nevirapine is an inducer of the CYP3A4 isoenzymes, and it increases the
metabolism of a number of drugs, such as oral contraceptives, ketoconazole,
methadone, quinidine, and warfarin.

Retroviral protease inhibitors (PIs)

Retroviral protease inhibitors (PIs)
● Six protease inhibitors—Atazanavir (ATV), Indinavir (IDV), Nelfinavir (NFV),
Saquinavir (SQV), Ritonavir (RTV) and Lopinavir have been marketed in India
for use against HIV.
● They act at a late step of viral cycle, they are effective in both newly as well as
chronically infected cells.
● Under their influence, HIV-infected cells produce immature noninfectious viral
progeny—hence prevent further rounds of infection.

Protease Inhibitors
● Oral bioavailability of PIs is variable
※ Oral bioavailability of IDV and RTV is 65%,
※ Oral bioavailability of NFV is >20%,
※ Oral bioavailability of SQV is 15%
● Plasma t½ ranges from 2–8 hours
● All are extensively metabolized mainly by CYP3A4

Protease Inhibitors
● The most prominent adverse effects of Pis are gastrointestinal intolerance,
asthenia, headache, dizziness, limb and facial tingling, numbness and
rashes.
● Of particular concern are lipodystrophy (abdominal obesity, buffalo hump with
wasting of limbs and face), dyslipidaemia (raised triglycerides and cholesterol)
which may necessitate hypolipidaemic drugs, and insulin resistance
● Indinavir crystalises in urine and increases risk of urinary calculi.

Enfuvirtide
● This HIV-derived synthetic peptide acts by binding to HIV-1 envelope transmembrane
glycoprotein (gp41)
● HIV-1 envelope transmembrane glycoprotein (gp41) is involved in fusion of viral and cellular
membranes.
● Fusion of the two membrances is thus prevented and entry of the virus into the cell is blocked.
● It is not active against HIV-2.
● No cross resistance with other classes of ARV drugs occurs.
● Administered s.c. twice daily.
● The injections are painful and cause local nodules/cysts.

Maraviroc
● The globular glycoprotein of the HIV envelope anchors to the CD4 site of host cell
by binding to a cell membrane receptor, which mostly is the CCR5 chemokine
receptor (most HIV are CCR5-tropic).
● Maraviroc is a novel anti- HIV drug which targets the host cell CCR5
receptor and blocks it.
● Attachment of the virus and subsequent entry of viral genome into the cell is thus
interfered.
● It has no effect on HIV strains that are CXCR4 receptor tropic
● It is active orally and there is no cross resistance with any other ARV drug

Raltegravir
● The HIV-proviral DNA transcripted in the cytoplasm of host cell, which
translocates to the nucleus along with an integrase enzyme
● The HIV-integrase nicks host chromosomal DNA and integrates the proviral DNA
with it.
● Raltegravir is an orally active drug that blocks this step by inhibiting the integrase
enzyme.
● It is active against both HIV-1 and HIV-2.
● Because of its unique mechanism of action, there is no cross resistance between
it and any other ARV drug

Antiviral drugs

More Related Content

What's hot

Similar to Antiviral drugs

More from Jegan Nadar

Recently uploaded

Antiviral drugs