Antiviral Drugs

o Viruses are obligate intracellular parasites.

o lack both a cell wall and a cell membrane.

o They do not carry out metabolic

processes.

o Viruses use much of the host’s metabolic

machinery.

o Few drugs are selective enough to prevent

viral replication without injury to the

infected host cells.

Structure of viruses

• Consist of two basic components: nucleic acid

(single- or double-stranded RNA or DNA) -

never both

• Surrounded by protein coat: “capsid” and

sometimes an outer lipid “envelope”

• A fully assembled infectious virus: “virion”

• Often contain crucial virus-specific enzymes

• Often visible by electron microscopy

Antiviral Drugs Therapy for viral diseases is further complicated

because:

o The clinical symptoms appear late in the course of

the disease, at a time when most of the virus

particles have replicated.

o At this stage of viral infection, administration of drugs

that block viral replication has limited effectiveness.

o Some antiviral agents are useful as prophylactic

agents.

o Antiviral drugs share the common property of being

virustatic; they are active only against replicating

viruses and do not affect latent virus.

General anti-viral strategies are to

inhibit:

oViral attachment to host cell,

o Penetration.

oUncoating

oViral enzymes:

DNA/RNA polymerases, etc.

Reverse transcriptases, proteases, etc.

oRelease of virus from cell surface

membranes

Treatment of Herpes virus Infections

• Herpes viruses are associated with a

broad spectrum of diseases, for example,

cold sores, viral encephalitis, and genital

infections.

• The drugs that are effective against

these viruses exert their actions during

the acute phase of viral infections and are

without effect during the latent phase.

Acyclovir • Acyclovir (acycloguanosine) is the prototypic

antiherpetic therapeutic agent. Herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV).

• It is the treatment of choice in HSV encephalitis.

• The most common use of acyclovir is in therapy for genital herpes infections.

• 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 – Structure • Purine Mimic

• Similarity to 2`-deoxyguanosine

(dGTP): lack of 3` hydroxyl

Acyclovir - MOA

Step 1: Activation

Acyclovir – MOA (Summary)

Acyclovir

Acyclovir Monophosphate

Acyclovir triphosphate

Herpes virus specific thymidine

kinase

Cellular

kinases

Inhibits herpes virus DNA Polymerase competitively

Gets incorporated in viral DNA and stops lengthening of DNA strands. The terminated DNA Inhibits DNA-polymerase irreversibly

• Adverse effects: • Side effects of acyclovir treatment depend on the

route of administration.

• Local irritation may occur from topical application.

• After oral administration. headache, diarrhea, nausea,

and vomiting may result.

• Transient renal dysfunction may occur at high doses

or in a dehydrated patient receiving the drug

intravenously.

• Resistance: Altered or deficient thymidine kinase and

DNA polymerases have been found in some resistant

viral strains and are most commonly isolated from

immunocompromised patients.

• Cross resistanc to the other agents in this family occurs.

Adamantane Antivirals • The therapeutic spectrum of the adamantane derivatives:

Amantadine

Rimantadine

• Influenza A infections.

• Due to widespread resistance, the adamantanes are not

recommended in the United States for the treatment or

prophylaxis of influenza A.

• Mechanism of action: Amantadine and rimantadine

interfere with the function of the viral M2 protein, possibly

blocking uncoating of the virus particle and preventing viral

release within infected cells.

o Amantadine is mainly associated with

CNS adverse effects, such as insomnia, dizziness, and ataxia.

More serious adverse effects may include hallucinations and seizures.

Amantadine should be employed cautiously in patients with psychiatric problems, cerebral atherosclerosis, renal impairment, or epilepsy.

o Rimantadine causes fewer CNS reactions. Both drugs cause GI intolerance.

• They should be used with caution in pregnant and nursing mothers.

Resistance: • Resistance can develop rapidly, and resistant strains can be

readily transmitted to close contacts.

• Resistance has been shown to result from a change in one amino acid of the M2 matrix protein.

• Cross-resistance occurs between the two drugs.

Neuraminidase Inhibitors Mechanism of action:

• 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.

Neuraminidase Inhibitors o Oseltamivir

o Zanamivir

o Both are effective against both type A and type B

influenza viruses.

o They do not interfere with the immune response

to influenza vaccine.

o Administered prior to exposure,

neuraminidase inhibitors prevent infection and,

when administered within 24 to 48 hours after

the onset of symptoms, they modestly decrease

the intensity and duration of symptoms.

Adverse Effects o Oseltamivir: gastrointestinal (GI) discomfort and nausea, which

can be alleviated by taking the drug with food.

o Zanamivir: irritation of the respiratory tract occurs with.

o It should be used with caution in individuals with asthma or

chronic obstructive pulmonary disease, because bronchospasm

may occur.

Resistance: o Mutations of the neuraminidase enzyme have been identified in

adults treated with either of the neuraminidase inhibitors.

o These mutants, however, are often less infective and virulent

than the wild type.