Anti Viral agents for 2016.pdf

Anti Viral agents 1/27/2024 By FA 1  Antiviral agents are drugs that cure or control virus infections. Unlike antibacterial drugs, which may cover a wide range of pathogens, antiviral agents tend to be narrow in spectrum, and have limited efficacy. As a class...

Anti Viral agents 1/27/2024 By FA 1  Antiviral agents are drugs that cure or control virus infections. Unlike antibacterial drugs, which may cover a wide range of pathogens, antiviral agents tend to be narrow in spectrum, and have limited efficacy. As a class, the antiviral drugs are not usually curative, and must be used either prophylactically or early in the development of an infection 1/27/2024 By FA 2  Strategies for Antiviral Therapy Any stage of viral replication with the following requirements can be a target for antiviral drugs. – The stage targeted is essential for virus replication. – The therapeutic agent is active against the virus while having "acceptable toxicity" to the host organism Stages in Virus Replication which are Possible Targets for Chemotherapeutic Agents Attachment to host cell. Uncoating - (Amantadine). Replication of viral RNA or DNA - (Nucleoside analogues). Synthesis of viral mRNA - (Interferon) Translation of mRNA - (Interferon). Maturation of new virus proteins (Protease inhibitors).- Budding, release. 1/27/2024 By FA 3 1/27/2024 By FA 4 Classification of Antivirals Antivirals effective against influenza virus. Antivirals effective against herpes virus. Antivirals effective against respiratory syncytial virus. Antivirals effective against hepatitis C and B. Antivirals effective against HIV virus. 1/27/2024 By FA 5  Antiviral Agents Effective Against Influenza Viruses A. Agents Effective Against Influenza Virus Type A Adamentane Derivatives i. Amantadine HCl (Adamine) ii. Rimantadine HCl (Flumadine) H3C NH2.HCl NH2.HCl 1-Adamantanamine -Methyl-adamantanemethylamine Hydrochloride hydrochloride The clinical usefulness of amantadine and rimantadine is limited to the prevention and treatment of influenza A virus infections. Amantadine is excreted by the kidneys unchanged via glomerular filtration and tubular secretion while rimantadine is metabolized by the liver (75%) and is also excreted by the kidneys. Rimantadine also has a longer duration of action. 1/27/2024 By FA 6  MOA The two drugs inhibit the early stages of viral replication, blocking the uncoating of the viral genome and the transfer of nucleic acid into the host cells. Amantadine inhibits also virus particle penetration into the host cells. 1/27/2024 By FA 7  Agents Effective against Virus Influenza Types A and B Neuraminidase Inhibitors (Sialic Acid Analogs) Zanamivir Oseltamivir HO OH H O COOC2H5 HO O 3 H3CCONH COOH 4 5 HN HN NH2. H3PO4 O NH2 N H The neuraminidase inhibitors, zanamivir and oseltamivir, are chemically related drugs that have activity against both influenza A and B viruses. Zanamivir is an orally inhaled powdered drug that is approved for treatment of influenza in persons aged 7 years and older. Zanamivir is not approved for chemoprophylaxis of influenza. Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate Oseltamivir is an orally administered capsule or oral suspension that is approved for treatment of influenza in persons aged 1 year and older. – It is also approved for chemoprophylaxis of influenza in persons aged 13 years and older. 1/27/2024 By FA 8  Mechanism of Action o Influenza viruses are surrounded by a protein coat and a lipid envelope. o Embedded in the lipid membrane there are two surface glycoproteins: Hemaglutinin (HA) is an enzyme important for binding viruses to target cell receptor via a terminal sialic acid residue. Neuraminidase (NA) an enzyme involved in various activation of influenza viruses. – NA is found in both influenza A and B and is thought to be involved in catalytically cleaving glycosidic bonds between terminal sialic acid and an adjacent sugar. – The cleavage of sialic acid bonds facilitates the spread of viruses and as a result increases the infectiveness or pathogenicity of the virus. – NA inhibitors interfere with the spread of the infection by blocking sialic acid bonds cleavage. 1/27/2024 By FA 9  Negatively charged at neutral pH R = Carbohydrate HO HO OH OH HO CO2H HO CO2H O O Neuraminidase H OH H OR + ROH AcNH H2O AcNH OH OH Sialic Acid (also: N-acetylneuraminic acid) 1/27/2024 By FA 10  Antiviral Agents Effective Against Herpes Virus The family of herpes virus includes:  Herpes simplex types 1 and 2 (HSV1, HSV2), Varicella Zoster (VZV) and Epstein Bar (EBV).  Cytomegalovirus (CMV). A) Agents Effective Against HSV1 and 2, VZV and EBV – Drugs in this class are Nucleotide analogues with sugar modification. – They resemble natural nucleotides, but have an incomplete ribose group. – They act as DNA polymerase inhibitors. i. Acyclovir (Zovirax) ii. Valacyclovir HCl 1/27/2024 By FA 11  i. Acyclovir (Zovirax) O ii. Valacyclovir HCl O N HN N HN H2N N N N NH2. HC l H2 N N OH O O CH(C H3)2 O 9-[(2-Hydroxyethoxy)methyl]guanine H O Acyclovir is a synthetic analog of the normal metabolite 2’- Deoxyguanosine. Valacyclovir is a valine ester of acyclovir that is well absorbed. Its bioavailability is 2-5 greater than acyclovir. So low dose is possible at less frequent intervals. It is used for the treatment and suppression of genital herpes infection. Acyclovir is most active against HSV but also has activity against VZV with little activity against EBV 1/27/2024 and no activity against CMV. By FA 12 MOA They are phosphorylated to the monophosphate by viral thymidine kinase and then to the di- then triphosphate by a host cell kinase. The triphosphate form of the drug blocks DNA replication of viral DNA by competitive inhibition of viral DNA polymerase and incorporation and termination of the growing viral DNA chain. Chain termination occurs because the drug triphosphate lacks the 3-hydroxy group of cyclic sugar. 1/27/2024 By FA 13 Selectivity of Action These drugs reduce DNA synthesis in virus-infected cells without affecting the active replication of uninfected cells because: – Viral thymidine kinase phosphorylates the drug over 100 times faster than host cells (differential toxicity). – Acyclovir triphosphate competitively inhibits viral DNA polymerases, and to a much smaller extent cellular DNA polymerases. 1/27/2024 By FA 14 Other Drugs Used as Topical Applications for Herpes Tifluridine (R=CF3), 2'-deoxy-5-(trifluoromethyl) uridine Idoxuridine (R = I), 2'-deoxy-5-iodouridine – These are pyrimidine analogs with base modification – Are only suitable for topical use. O R HN O N O HO HO 1/27/2024 By FA 15 Agents Effective Against Cytomegalovirus (CMV) Ganciclovir 9-[1,3-Dihydroxy-2-propoxymethyl]guanine Ganciclovir is a deoxyguanosine analog that differs from acyclovir in having an additional hydroxymethyl group on the acyclic side chain. It is the preferred drug for treating (CMV) infections in patients with acquired immune deficiency syndrome (AIDS) or other immunodeficiencies. It has very poor oral bioavailability (3 percent), and, therefore, mostly given intravenously. 1/27/2024 By FA 16 MOA It is an acyclic guanine nucleoside analog and is activated to the nucleoside triphosphate that incorporates into new viral DNA and inhibits DNA polymerase. CMV is deficient in thymidine kinase this is why acyclovir has no activity against CMV. CMV may phosphorylate this drug by using UL97 gene product Selectivity is achieved because the viral polymerase has 30 times greater affinity for ganciclovir than the host enzyme. 1/27/2024 By FA 17 Cidofovir –active against the virus with no thyiamidine kinase 1/27/2024 By FA 18  Foscarnet (Foscavir) Foscarnet It is trisodium phosphonoformate It is the drug used in the treatment of CMV infections, particularly CMV retinitis, in immunocompromised patients. O P 3 Na O COO Mechanism of action O It is an Inorganic pyrophosphate analog that works by reversibly blocking the pyrophosphate binding site on viral DNA polymerase, thereby terminating chain elongation. Unlike nucleoside analogs, foscarnet does not need to be activated by cellular or viral kinases. 1/27/2024 By FA 19  Anti-HIV Agents Billions of dollars have been spent on research and development of anti–AIDS drugs, the disease remains uncontrolled. Over 30 million people infected worldwide with HIV. Therapy of HIV is complicated by the ability of the virus to mutate leading to rapid drug resistance. Although a number of substances with in vitro anti-HIV activity have been described, only a few drugs exhibit anti-HIV activity in vivo at tolerable toxicities. 1/27/2024 By FA 20 HIV target o Cells containing more number of CD4 cells o T4-lymphocyte (also called the "T-helper cell"), a kind of white blood cell that has lots of CD4 receptors. o The T4-cell is responsible for warning your immune system that there are invaders in the system 1/27/2024 By FA 21  Life cycle of HIV Step 1: Attachment of virus at the CD4 receptor and chemokine co-receptors CXCR4 or CCR5 Step 2: viral fusion and uncoating Steps 3-5: Reverse transcriptase makes a single DNA copy of the viral RNA and then makes another to form a double stranded viral DNA Step 6: migration to nucleus Steps 7-8: Integration of the viral DNA into cellular DNA by the enzyme integrase Steps 9-11: Transcription and RNA processing Steps 12-13: Protein synthesis Step 14: protease cleaves polypeptides into functional HIV proteins and the virion assembles Step 15: virion budding Step 16: Virion maturation 1/27/2024 By FA 22  ANTI-HIV AGENTS Anti-HIV agents can be grouped into three groups 1. Pretranscription inhibitors  Inhibitors of gp120 binding to CD4  inhibitors of gp120 binding to coreceptors  inhibitors of viral fusion and viral uncoating. 2. The transcription inhibitors-inhibit reverse transcriptase -the nucleoside reverse transcriptase inhibitors (NRTIs) and the nonnucleoside reverse transcriptase inhibitors (NNRTIs). 3. The posttranscription inhibitors 1/27/2024 By FA 23  The most challenging problem associated with HIV therapy is the development of Resistance  The combination therapy approach has been broadly practiced in HIV treatment as a strategy to avoid such problem development of drug resistance.  Current efforts to develop new anti-HIV drugs are now directed more toward developing inhibitors for other steps in the virus life cycle such as  viral entry into the T-cell,  its integration with the host DNA, or  its assembly into daughter particles. These proposed sites of intervention may provide additional options to maintain long-term suppression of the virus replication 1/27/2024 By FA 24  Inhibitors of Viral Entry HIV Vaccines The most ideal approach to inhibit HIV binding to the T- cells is to develop a vaccine that can neutralize the virus in circulation. Several attempts to develop antibodies to HIV as blocker for the viral binding to prevent infection have been reported. However, because of the nature of the disease, people infected with HIV develop only low titers of neutralizing antibodies and that presents a problem for vaccine development. 1/27/2024 By FA 25  Inhibitors of Viral Entry… Viral Adsorption Inhibitors The recognition of the role of viral gp120 and gp41 glycoproteins in the processes of HIV binding and fusion with the T-cell surface flagged these sites as an attractive molecular target for intervention. In principle, agents affecting any of the viral entry events would be effective as inhibitors of HIV-1 replication. Targets of viral entry inhibition and fusion include the process of gp120 binding to CD4 receptors and other coreceptors (CCR5, CXCR4) on the T- cell membrane. 1/27/2024 By FA 26  Inhibitors of Viral entry… A. polyanaionic compounds Several polyanionic compounds of natural and synthetic sources have been reported to inhibit gp120 binding to the cell membrane. Among these anionic compounds are polysulfates, polysulfonates, and polycaroxylates. All are believed to exert their antiviral activity through inhibiting gp120 binding to the CD4 receptor 1/27/2024 By FA 27  Inhibitors of viral entry… B. Inhibitors of Gp120 Binding to the T-cell Coreceptors CXCR4 and CCR5 are Gp120 Coreceptors which are found on Tcell membrane surface The most interesting member of Gp120-CXCR4 Binding Inhibitor is the compound bicyclam (AMD3100) 1/27/2024 By FA 28 Additional CXCR4 inhibitors in preclinical studies include the polypeptide derivatives ALX40-4C TAK-779 is a potent Gp120-CCR5 Binding Inhibitor which is under clinical trial 1/27/2024 By FA 29  Inhibitors of Viral Fusion The fusion of the virus envelope with the Tcell membrane commences after the binding of gp120 to the coreceptors CXCR4 and CCR5. This binding triggers a spring-loaded action of the glycoprotein gp41, which is normally covered by the larger gp120. The gp41 anchors itself to the T-cell membrane through the hairpin structures HR1 and HR2 The betulinic acid derivative RPR103611 reperesent a nonpeptide inhibitor for gp41 fusion. 1/27/2024 By FA 30  Inhibitors viral fusion Enfuvirtide-The first compound to be approved for clinical use for HIV 1 infection  Oligopeptide with 36 aminoacids  Structurally simillar with HR2 of gp41  Maraviroc-clinically Approved CCR5 antagonist orally given with low oral bioavailability due to N-dealkylated inactive matabolism 1/27/2024 By FA 31  lnhibitors for Viral Uncoating The viral uncoating process (loss of its nucleo protien outer coat after fusion) results in release of its RNA genome into the cytoplasm. A number of uncoating inhibitors are reported some of which are listed below 1/27/2024 By FA 32 Currently availabe Anti Retroviral Agents are classified into three groups  Nucleoside analogs reverse transcriptase inhibitors (NRTI).  Non-nucleoside analogs reverse transcriptase inhibitors (NNRTI).  HIV Protease inhibitors. 1/27/2024 By FA 33 Nucleoside Reverse Transcriptase Inhibitors (NRTls) Act as irreversible, competitive inhibitors for the HIV RT. 1/27/2024 By FA 34 Zidovudine was the first antiviral agent shown to have beneficial effect against HIV infection.  After prolonged use, AZT-resistant strains rapidly appears which limits the effect of AZT.  It is an analog of thymidine in which the azido group is substituted at the 3 carbon atom of the dideoxyribose moiety.  Stavudine differs in structure from thymidine by replacement of the 3’hydroxyl group with a hydrogen atom and a double bond in the 2’and 3’ positions of deoxyribose ring. Lamivudine is an analog of 2’-deoxycytidine in which the 3’- methylene group of deoxyribose ring is replaced with a sulfur atom. Didanosine is a purine dideoxynucleoside which is an analog of inosine. 1/27/2024 By FA 35 MOA They are first bioactivated to triphosphate by cellular kinase. These phosphates act as: - Competitive inhibitor of viral reverse transcriptase. -Chain terminators. They are incorporated into viral DNA and viral DNA synthesis which is terminated because these drugs lack a 3’–OH group, consequently no more phosphodiester bonds could be formed. Selectivity of Action These drugs are less susceptible to mammalian DNA polymerase. Viral reverse transcriptase is 100 times more susceptible to inhibition by zidovudine triphosphate than host cellular DNA polymerase. 1/27/2024 By FA 36  Non Nucleoside Analogues Reverse Transcriptase Inhibitors (NNRTI) FDA has recently approved several NNRTI. They should not be used as monotherapy but they are used with NRTI to obtain synergistic activity in decreasing viral load and increasing CD4+ cell counts. H O CH3 F3 C N C C Cl O N N N N O H Nevirapine Efavirenz 1/27/2024 By FA 37 MOA These drugs noncompetitively inhibit viral RT, presumably by binding to a site other than the nucleoside and template binding sites (allosteric site}. This interaction between the NNRTI and the HIV-1 RT produces a conformational change that results in the inactivation of the viral RT. Toxicity includes rash and CNS toxicity as dizziness, insomnia and impaired concentration. 1/27/2024 By FA 38  Viral Integrase Inhibitors Raltegravir is approved only for use only in individuals whose infection has proven resistant to other HAART drugs. As with any HAART medication, raltegravir is unlikely to show durability if used as monotherapy. Raltegravir is taken orally twice daily. 1/27/2024 By FA 39  Protease Inhibitors 1/27/2024 By FA 40  Inhibitors of this viral protease can be used to fight HIV infection.  By blocking the ability of protease to cleave the viral polypeptide into functional enzymes, protease inhibitors interfere with continued infection.  Most current protease inhibitors are complex peptidomimetic compounds with poor aqueous solubility, low bioavailability and short plasma half-lifes.  The complexity of these agents not only contributes to their high cost but also increases the potential for unwanted drug interactions.  Four protease inhibitors, saquivanir (Invirase®, Hoffman- LaRoche), ritonavir (Norvir®, Abbott), indinavir (Crixivan®, Merck) and nelfinavir (Viracept®, Agouron) have already been approved. 1/27/2024 By FA 41 First generation Pis 1/27/2024 By FA 42 1/27/2024 By FA 43 The aim of anti-HIV therapy has now shifted from simply delaying the progression of the disease to finding a permanent cure. We have now entered the area of highly active anti-retroviral therapy (HAART). The current trend is to give a potent combination of agents HAART right from the start when treatment is indicated. 1/27/2024 By FA 44  The most popular combination is AZT and lamivudine plus a protease inhibitor.  Lamivudine has greater anti-retroviral activity than AZT alone and is active against many AZT-resistant strains without significant increase in toxicity.  Among protease inhibitors, indinavir (IDV) is more potent than saquinavir and appears to have fewer drug interactions and short-term adverse effects than ritonavir. 1/27/2024 By FA 45