VIRUS

Professor Viru Sahastrabudhhe

“ Virus " VIRUS VIRUS in computer…??

ƒ A VIRUS is a program or programming code that replicates ƒ Attaches itself to a file enabling it to spread from one computer to another, leaving as it travels Can CONTROL your system…. Can show MESSAGES.. Can DAMAGE your files…

ANTIVIRUS PROGRAMME ANTIVIRAL AGENTS

Dr Satyajit , MD Asst Professor Dept of Pharmacology Viruses

Obligate intracellular parasites Consist of a core genome in a protein shell and some are surrounded by a lipoprotein Lack a cell wall and cell membrane Do not carry out metabolic processes Replication depends on the host cell machinery For replication it has to attach a cell

Steps for Viral Replication

ƒ Binding of the virus to the host cell ƒ Penetration into the host cell ƒ Un-coating of the virion ƒ Reverse ƒ Entry of DNA into the nucleus ƒ Transcription of provirus into mRNA ƒ mRNA translation by host ribosomes ƒ Assembly & budding ƒ Release of new virions

Classification

1. Anti-Herpes virus Idoxuridine Acyclovir Valacyclovir Famciclovir Ganciclovir * *

* Not marketed in India Anti-Retrovirus a) Nucleoside inhibitors (NRTIs) (AZT) b) Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz c) Protease inhibitors Anti-Influenza Drugs

Amantadine Rimantadine Nonselective Antiviral Drugs

ƒ Ribavirin ƒ Lamivudine ƒ Interferon 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

ƒ Acyclovir - prototype ƒ Valacyclovir ƒ Famciclovir ƒ Penciclovir ƒ Trifluridine ƒ Vidarabine 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

ƒ Herpes simplex I – most sensitive

ƒ HSV II > VZV = EBV

ƒ CMV not affected Acyclovir

ƒ Oral, IV, and Topical

ƒ t ½ = 3-4 hr

ƒ Cleared by glomerular filtration and tubular secretion Acyclovir- Uses

¾ Herpes Simplex Virus 1 and 2 (HSV)

¾ Varicella-zoster virus (VZV) Genital Herpes simplex

By type II HSV

Topical /oral / parenteral

Primary disease - Early 5% ointment locally 6 times a day for 10 days

Late cases – 400mg TDS oral 10d Mucocutaneous H.simplex

Oral/IV 15 mg/kg/day for 7 days H.Simplex keratitis

Better for deep stromal 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

ƒ Stinging and burning sensation - topical

ƒ Nausea, diarrhea - oral

ƒ Headache

ƒ Tremors

ƒ Skin rash and delirium

ƒ Dose dependent decrease in GFR Valacyclovir

ƒ L-valyl ester of acyclovir

ƒ Converted to acyclovir when ingested

ƒ M.O.A.: same as acyclovir

ƒ Uses:

¾ 1) recurrent genital herpes

¾ 2) herpes zoster infections

ƒ Side Effects: nausea, diarrhea, and headache Famciclovir

ƒ Prodrug of penciclovir

ƒ A guanosine analogue

ƒ M.O.A.: same as acyclovir

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

ƒ Side Effects: nausea, diarrhea, and headache Idoxuridine

ƒ Thymidine analog

ƒ Competes with thymidine & gets incorporated in DNA

ƒ Formation of faulty DNA

ƒ Synthesis of wrong viral proteins

ƒ Unwanted effect

¾ Bone marrow depression Trifluridine (5-iodo-2-deoxyuridine)

ƒ Trifluridine- fluorinated pyrimidine

¾ inhibits viral DNA synthesis same as acyclovir

¾ incorporates into viral and cellular DNA

¾ 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)

9 GancIclovir

9 Foscarnet

9 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 Foscarnet

ƒ An inorganic pyrophosphate

ƒ Inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase

ƒ Does not have to be phosphorylated

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

ƒ Resistance due to mutations in DNA polymerase

ƒ Side Effects: hypo- or hypercalcemia ,phosphotemia Fomivirsen

ƒ An oligonucleotide

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

ƒ Uses: CMV retinitis

ƒ Side effects: Iritis and increased IOP Anti retroviral Drugs HUMAN IMMUNE DEFICIENCY VIRUS Human immunodeficiency virus

Virus classification ƒ Group: Group VI (ss RNA-RT) ƒ Family: Retroviridae ƒ Genus: Lentivirus ƒ Species z Human immunodeficiency virus 1 z Human 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

ƒ Roughly spherical ƒ About 120 nm ƒ ss-RNA ƒ Nucleocapsid- p 24 ƒ Matrix – p 17 ƒ Envelope protein – gp 120,

ƒ Enzymes – RT, Integrase, Proteases HIV tropism

¾ CD4+ cells 1. T helper cells 2. Macrophage/Monocytes 3. Microglial cells 4. Langerhan cells ¾ Co receptors 1. CCR5 – β chemokines (MCP1, RANTES) 2. CXCR4 – α chemokines (SDF 1) The HIV replication cycle Classes of Antiretroviral drugs

ƒ Nucleoside and nucleotide reverse transcriptase inhibitors (nRTI) ƒ Non-nucleoside reverse transcriptase inhibitors (NNRTI) ƒ Protease inhibitors (PIs) ƒ Integrase inhibitors ƒ Entry inhibitors ( fusion inhibitors) ƒ Maturation inhibitors ƒ Broad spectrum inhibitors Nucleoside and nucleotide reverse transcriptase inhibitors (nRTI)

ƒ Zidovudine (AZT) ƒ Didanosine (ddI) ƒ Lamivudine (3TC) ƒ Stavudine (d4T) ƒ Zalcitabine (ddC) ƒ Abacavir (ABC) ƒ (FTC)

# , , , , . NtRTIs - Tenofovir

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 Nevirapine Delavirdine Diarylpyrimidines (, ) Mechanism of Action NNRTIs

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)

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

ƒ Delavirdine - teratogenic

ƒ 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

ƒ Diarrhea ƒ Nausea ƒ Fatigue ƒ headache Saquinavir

ƒ A synthetic peptide-like substrate analog

ƒ Inhibits HIV-1 protease

ƒ Prevents cleavage of viral polyproteins 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

ƒ gp41 -

ƒ CCR5 - , †, PRO 140†

ƒ CD4 - †

† Undergoing clinical trials, not FDA approved Integrase inhibitors

ƒ

ƒ #

# Phase III trials Maturation inhibitors

Bevirimat a drug designed to halt the development of immature HIV particles after they have emerged from human cells . HAART ????

Highly Active Anti Retroviral Therapy ƒ Treatment should be aggressive

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

ƒ With 3 ARDs is optimal

ƒ Choice is based on efficacy, durability, tolerability and cost 9 3 drugs in regimen should belong to at least 2 different groups 9 NRTI + NRTI + NNRTI 9 NRTI + NRTI + PI

9 3 NRTI regimen is employed when a NNRTI/PI cant be used

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

9 3 class regimen for advances cases HAART

ƒ Combination of three or more antiretroviral drugs

The preferred initial regimens are:

w efavirenz + zidovudine + lamivudine

w efavirenz + tenofovir + emtricitabine

w lopinavir boosted with ritonavir + zidovudine + lamivudine

w lopinavir boosted with ritonavir + tenofovir + emtricitabine HIV Post exposure Prophylaxis [PEP]

ƒ 28-day HIV drug regimen

ƒ 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 .

ƒ 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

9 Saquinavir 9 Ritonavir 9 Abacavir 9 Nelfinavir

Abacavir – a NRTI Which of the following PIs cause nephrolithiasis ?

ƒ Ritonavir ƒ Nelfinavir ƒ Ritonavir ƒ Indinavir

Indinavir Which of the following is not affected by Acyclovir

9 HSV

9 EBV

9 VZV

9 CMV

CMV

Anti-Hepatitis Agents

ƒ Lamivudine

ƒ

ƒ Interferon Alfa

ƒ Pegylated Interferon Alfa

ƒ Ribavirin Interferons

9 Interferon Alfa 9 Endogenous proteins

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

9 Bind to membrane receptors on cell surface

9 May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release Anti-Influenza Agents

ƒ Amantadine

ƒ Rimantadine

ƒ Zanamivir Amantadine and Rimantadine

¾ Cyclic amines

¾ It blocks the viral membrane protein, M2 which functions as ion channel

¾ used in the prevention and treatment of Influenza A

Any other use of Amantadine..???

Parkinsonism UNMASKED Treatment

ƒ Tamiflu (oseltamivir)

ƒ Relenza (zanamivir)

April 27, 2009, the Food and Drug Administration (FDA) issued Emergency Use Authorizations to make available Relenza and Tamiflu Remember…

ƒ Acyclovir

ƒ Antiretroviral drugs ***

ƒ Zidovudine

ƒ HAART therapy

ƒ Antiinfluenza drugs Thank you