VIRUS
Professor Viru Sahastrabudhhe
“ Virus " VIRUS VIRUS in computer…??
A VIRUS is a program or programming code that replicates Attaches itself to a file enabling it to spread from one computer to another, leaving infections 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
Binding of the virus to the host cell Penetration into the host cell Un-coating of the virion Reverse transcription Entry of DNA into the nucleus Transcription of provirus into mRNA mRNA translation by host ribosomes Assembly & budding Release of new virions
Classification
1. Anti-Herpes virus Idoxuridine Acyclovir Valacyclovir Famciclovir Ganciclovir * Foscarnet *
* Not marketed in India Anti-Retrovirus a) Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine (AZT) Didanosine Zalcitabine Stavudine Lamivudine Abacavir b) Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz Nevirapine Delavirdine c) Protease inhibitors Ritonavir Indinavir Saquinavir Amprenavir Lopinavir Anti-Influenza Drugs
Amantadine Rimantadine Nonselective Antiviral Drugs
Ribavirin Lamivudine 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
Acyclovir - prototype Valacyclovir Famciclovir Penciclovir Trifluridine 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
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
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 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:
¾ 1) recurrent genital herpes
¾ 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
¾ Bone marrow depression Trifluridine (5-iodo-2-deoxyuridine)
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
An 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 classification Group: Group VI (ss RNA-RT) Family: Retroviridae Genus: Lentivirus 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
Roughly spherical About 120 nm ss-RNA Nucleocapsid- p 24 Matrix – p 17 Envelope protein – gp 120,
gp41 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
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 Nucleoside and nucleotide reverse transcriptase inhibitors (nRTI)
Zidovudine (AZT) Didanosine (ddI) Lamivudine (3TC) Stavudine (d4T) Zalcitabine (ddC) Abacavir (ABC) Emtricitabine (FTC)
# Apricitabine, Stampidine, Elvucitabine , Racivir, Amdoxovir. 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 (Etravirine, Rilpivirine) Loviride 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)
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
Diarrhea Nausea Fatigue headache 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
Elvitegravir #
# 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 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 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
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]
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
9 Saquinavir 9 Ritonavir 9 Abacavir 9 Nelfinavir
Abacavir – a NRTI Which of the following PIs cause nephrolithiasis ?
Ritonavir Nelfinavir Ritonavir Indinavir
Indinavir Which of the following is not affected by Acyclovir
9 HSV
9 EBV
9 VZV
9 CMV
CMV
Anti-Hepatitis Agents
Lamivudine
Adefovir
Interferon Alfa
Pegylated Interferon Alfa
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
Amantadine
Rimantadine
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
Tamiflu (oseltamivir)
Relenza (zanamivir)
April 27, 2009, the Food and Drug Administration (FDA) issued Emergency Use Authorizations to make available Relenza and Tamiflu Remember…
Acyclovir
Antiretroviral drugs ***
Zidovudine
HAART therapy
Antiinfluenza drugs Thank you