VIRUS

Professor Viru Sahastrabudhhe

“ Virus "

VIRUS

V I R U S in computer…??

A V I R U S is a program or programming code thatreplicatesAttaches itself to a file enabling it to spread from onecomputer to another, leaving infections as it travels

Can CONTROL your system….

Can show MESSAGES..

Can DAMAGE your files…

ANTIVIRUS PROGRAMME

ANTIVIRAL AGENTS

Dr Satyajit , MDAsst Professor

Dept of Pharmacology

Viruses

Obligate intracellular parasitesConsist of a core genome in a protein shell and some are surrounded by a lipoproteinLack a cell wall and cell membraneDo not carry out metabolic processesReplication depends on the host cell machineryFor replication it has to attach a cell

Steps for Viral Replication

Binding of the virus to the host cellPenetration into the host cellUn-coating of the virionReverse transcriptionEntry of DNA into the nucleusTranscription of provirus into mRNAmRNA translation by host ribosomesAssembly & buddingRelease of new virions

Classification

1. Anti-Herpes virusIdoxuridineAcyclovir ValacyclovirFamciclovirGanciclovir *Foscarnet *

* Not marketed in India

Anti-Retrovirus

a) Nucleoside reverse transcriptase inhibitors (NRTIs)Zidovudine (AZT)DidanosineZalcitabineStavudineLamivudineAbacavir

b) Nonnucleoside reverse transcriptase inhibitors(NNRTIs)

EfavirenzNevirapineDelavirdine

c) Protease inhibitorsRitonavirIndinavirSaquinavirAmprenavirLopinavir

AmantadineRimantadine

Anti-Influenza Drugs

Nonselective Antiviral Drugs

RibavirinLamivudineInterferon α

Anti Herpes agents

Herpes viruses 2 type:-

Herpes simplex type I and II

Type I cause disease of mouth, face & skin

Type II affects genitals, rectum and skin

Vidarabine- 1st agent to be developed

Too toxic

Idoxuridine, Acyclovir, Famciclovir, Ganciclovir,

Foscarnet

HSV I

HSV II

Anti herpes Agents

Acyclovir - prototypeValacyclovirFamciclovirPenciclovirTrifluridineVidarabine

Mechanism of Action Acyclovir

An acyclic guanosine derivative

Phosphorylated by viral thymidine kinase

Di-and tri-phosphorylated by host cellular kinases

Inhibits viral DNA synthesis by:

1) competing with dGTP for viral DNA polymerase

2) chain termination

Activity against viruses

Herpes simplex I – most sensitive

HSV II > VZV = EBV

CMV not affected

Acyclovir

Oral, IV, and Topical

t ½ = 3-4 hr

Cleared by glomerular filtration and tubular secretion

Acyclovir- Uses

Herpes Simplex Virus 1 and 2 (HSV)

Varicella-zoster virus (VZV)

Genital Herpes simplex

By type II HSV

Topical /oral / parenteral

Primary disease - Early5% ointment locally6 times a day for 10 days

Late cases – 400mg TDS oral 10d

Mucocutaneous H.simplex

Oral/IV 15 mg/kg/dayfor 7 days

H.Simplex keratitis

Better for deep stromal infection

Eye ointment

5 times a day till 3 days after healing

Chikenpox

Immunodeficient and neonate

15mg/kg/day for 7 days is DOC

In susceptible contacts –

Oral Acyclovir 400 mg 4 times a day for 7 days

Side Effects: Acyclovir

Stinging and burning sensation - topical

Nausea, diarrhea - oral

Headache

Tremors

Skin rash and delirium

Dose dependent decrease in GFR

Valacyclovir

L-valyl ester of acyclovir

Converted to acyclovir when ingested

M.O.A.: same as acyclovir

Uses:

1) recurrent genital herpes

2) herpes zoster infections

Side Effects: nausea, diarrhea, and headache

Famciclovir

Prodrug of penciclovir

A guanosine analogue

M.O.A.: same as acyclovir

Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B

Side Effects: nausea, diarrhea, and headache

Idoxuridine

Thymidine analog

Competes with thymidine & gets incorporated in DNA

Formation of faulty DNA

Synthesis of wrong viral proteins

Unwanted effect

Bone marrow depression

Trifluridine (5-iodo-2-deoxyuridine)

Trifluridine- fluorinated pyrimidine

inhibits viral DNA synthesis same as acyclovir

incorporates into viral and cellular DNA

Uses: HSV-1 and HSV-2 (topically)

Vidarabine

An adenosine analog

Inhibits viral DNA polymerase

Incorporated into viral and cellular DNA

Metabolized to hypoxanthine arabinoside

Side Effects: GI intolerance, myelosuppression

Anti-Cytomegalovirus Agents (CMV)

GancIclovir

Foscarnet

Fomivirsen

Ganciclovir

An acyclic guanosine analog

Requires triphosphorylation for activation

M.O.A.: same as acyclovir

Uses: CMV*, HSV, VZV,and EBV

Side Effect: myelosuppression

FoscarnetAn inorganic pyrophosphate

Inhibits viral DNA polymerase, RNA polymerase, and

HIV reverse transcriptase

Does not have to be phosphorylated

Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV

Resistance due to mutations in DNA polymerase

Side Effects: hypo- or hypercalcemia ,phosphotemia

Fomivirsen

An oligonucleotide

M.O.A.: binds to mRNA and inhibits protein synthesis

and viral replication

Uses: CMV retinitis

Side effects: Iritis and increased IOP

Anti retroviral Drugs

HUMAN IMMUNE DEFICIENCY VIRUS

Human immunodeficiency virus

Virus classificationGroup: Group VI (ss RNA-RT)Family: Retroviridae

Genus: Lentivirus

SpeciesHuman immunodeficiency virus 1Human immunodeficiency virus 2

Comparison of HIV species

Species Virulence Transmittability Prevalence Purported origin

HIV-1 High High Global Common Chimpanzee

HIV-2 Lower Low West Africa Sooty Mangabey

STRUCTURE AND GENOME OF HIV

Roughly spherical

About 120 nm

ss-RNA

Nucleocapsid- p 24

Matrix – p 17

Envelope protein – gp 120,

gp41

Enzymes – RT, Integrase, Proteases

HIV tropism

CD4+ cells

1. T helper cells

2. Macrophage/Monocytes

3. Microglial cells

4. Langerhan cells

Co receptors

1. CCR5 – β chemokines (MCP1, RANTES)

2. CXCR4 – α chemokines (SDF 1)

The HIV replication cycle

Classes of Antiretroviral drugs

Nucleoside and nucleotide reverse transcriptase inhibitors (nRTI)

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

Protease inhibitors (PIs)

Integrase inhibitors

Entry inhibitors ( fusion inhibitors)

Maturation inhibitors

Broad spectrum inhibitors

Zidovudine (AZT)

Didanosine (ddI)

Lamivudine (3TC)

Stavudine (d4T)

Zalcitabine (ddC)

Abacavir (ABC)

Emtricitabine (FTC)

# Apricitabine, Stampidine, Elvucitabine , Racivir, Amdoxovir.

NtRTIs - Tenofovir

Nucleoside and nucleotide reverse transcriptase inhibitors (nRTI)

Clinical Uses Zidovudine

Available in IV and oral formulations

Activity against HIV-1 and HIV-2

Mainly used for treatment of HIV, decreases rate

of progression and prolongs survival

Prevents mother to newborn transmission of HIV

Other NRTIs

Didanosine- synthetic deoxy-adenosine analog; causes pancreatitis*

Lamivudine- cytosine analog

Zalcitabine- cytosine analog; causes peripheral neuropathy*

Stavudine- thymidine analog; causes peripheral neuropathy*

Abacavir- guanosine analog; more effective than the other agents; fatal hypersensitivity reactions can occur

Nonnucleoside Reverse Transcriptase Inhibitors

Efavirenz NevirapineDelavirdine

Diarylpyrimidines (Etravirine, Rilpivirine)Loviride

Mechanism of ActionNNRTIs

Bind to site on viral reverse transcriptase

Results in blockade of RNA dependent DNA

polymerase activity

Does not compete with nucleoside triphosphates

Does not require phosphorylation

Substrates and inhibitors of CYP3A4

b) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine - prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery

Delavirdine - teratogenic

Efavirenz- teratogenic

Protease Inhibitors

The protease enzyme cleaves precursor molecules to produce mature, infectious virions

These agents inhibit protease and prevent the spread of infection

These agents cause a syndrome of altered body fat distribution, insulin resistance and hyper-lipidemia

Protease Inhibitors- adverse effects

DiarrheaNauseaFatigueheadache

Saquinavir

A synthetic peptide-like substrate analog

Inhibits HIV-1 protease

Prevents cleavage of viral polyproteins

Nelfinavir and Amprenavir

M.O.A.: Specific inhibitors of the HIV-1 protease

Less cross-resistance with Amprenavir

Side Effects: diarrhea and flatulence

Amprenavir can cause Stevens-Johnson syndrome

Contraindications: inhibitor/substrate for CPY3A4

Entry Inhibitors

gp41 - Enfuvirtide

CCR5 - Maraviroc, Vicriviroc†, PRO 140†

CD4 - Ibalizumab †

† Undergoing clinical trials, not FDA approved

Integrase inhibitors

Raltegravir

Elvitegravir #

# Phase III trials

Maturation inhibitors

Bevirimata drug designed to halt the development of immature HIV particles after they have emerged from human cells .

HAART ????

Highly Active Anti Retroviral Therapy

Treatment should be aggressive

Suppress viral load to undetectable lebel - < 50 copies/ml

With 3 ARDs is optimal

Choice is based on efficacy, durability, tolerability and cost

3 drugs in regimen should belong to at least 2 different groups

NRTI + NRTI + NNRTINRTI + NRTI + PI

3 NRTI regimen is employed when a NNRTI/PI cant be used

PI sparing regimen more convenient with less pill burden, simple dose schedule

3 class regimen for advances cases

HAARTCombination of three or more antiretroviral drugs

The preferred initial regimens are:

efavirenz + zidovudine + lamivudine

efavirenz + tenofovir + emtricitabine

lopinavir boosted with ritonavir + zidovudine + lamivudine

lopinavir boosted with ritonavir + tenofovir + emtricitabine

HIV Post exposure Prophylaxis[PEP]

28-day HIV drug regimen

The minimum that should be used is dual NRTIs for 28

days, with triple therapy (dual NRTIs plus a boosted PI)

being offered where there is a risk of resistance .

Most effective the sooner the drugs are administered.

Mother-to-child transmission of HIV-1

The pregnant woman should start

Zidovudine (AZT) from 28 weeks or as soon as possible thereafter

single-dose Nevirapine (NVP) when entering labour

AZT+3TC for one week following delivery.

*Meanwhile, whether the mother was on the above or standard

ART, the child should be given single dose Nevirapine immediately

after delivery and daily Zidovudine until one week old .

ANSWER

………???

Which of the following is not a protease inhibitor

SaquinavirRitonavirAbacavirNelfinavir

Abacavir – a NRTI

Which of the following PIs cause nephrolithiasis ?

RitonavirNelfinavirRitonavirIndinavir

Indinavir

Which of the following is not affected by Acyclovir

HSV

EBV

VZV

CMV

CMV

Anti-Hepatitis Agents

Lamivudine

Adefovir

Interferon Alfa

Pegylated Interferon Alfa

Ribavirin

InterferonsInterferon AlfaEndogenous proteins

Induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA

Bind to membrane receptors on cell surface

May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release

Anti-Influenza Agents

Amantadine

Rimantadine

Zanamivir

Amantadine and Rimantadine

Cyclic amines

It blocks the viral membrane protein, M2 which functions as ion channel

used in the prevention and treatment of Influenza A

Any other use of Amantadine..???

Parkinsonism

UNMASKED

Treatment Tamiflu (oseltamivir)

Relenza (zanamivir)

April 27, 2009, the Food and Drug Administration (FDA)issued Emergency Use Authorizationsto make available Relenza and Tamiflu

Remember…

Acyclovir

Antiretroviral drugs ***

Zidovudine

HAART therapy

Antiinfluenza drugs

Thank you