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 Raltegravir 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