Viruses Treatment and prevention

1. Viruses Treatment and prevention

2. Anti-Viral Chemotherapy • Bacteria • Many antibiotics • Highly selective • Viruses • Use host cell metabolism • Selectivity difficult • Toxicity

3. Anti-Viral Chemotherapy • Key is selectivity • Other problems • Toxicity • Rapid excretion • Rapid metabolism • Poor absorption

4. Anti-Viral Chemotherapy Ideal Drug • Water soluble • Chemically and metabolically stable • Easily absorbed (apolar) • NOT • Toxic • Carcinogenic • Allergenic • Mutagenic • Teratogenic

5. Antiviral Drugs • Antiviral drugs include natural products of plants, synthetic oligonucleotides, oligosaccharides, simple inorganic and organic compounds and nucleoside analogues.

6. Adsorption peptide that mimics the receptor neutralizing antibody Penetration  amantadine Uncoating Biosynthesis nucleoside analogs Interferon gene therapy Assembly 、Release

7. Antiviral Mechanism of Antiviral Drugs • (1) Play Role on Cell-free Virus • (2) Block the Adsorption of Virus • (3) Block Virus Penetration and uncoating • (4) Interrupt the Transcription and translation of viral genome • (5) Translation • (6) Assembly

8. A. Chemotherapy

9. Nucleoside analogues核苷类药物 The majority of available agents are ～ herpesvirus inhibitors；anti-HIV agents； In addition to purine and pyrimidine nucleosides, ara-, amino-, aza-nucleosides or nucleotides have been synthesized.

10. Examples: • Acyclovir------－阿昔洛韦 • Ganciclovir------更昔洛韦（DHPG） • Idoxuridine------碘苷（IDU） • Zidovudine------齐多夫定（AZT）

11. Inhibitors of herpes DNA polymerase Acyclovir (a) be taken up only into infected cells (b) the actual inhibitory molecule be generated inside the infected cell by enzymatic activity (c) the inhibitor have a selective effect on a virus enzyme.

12. P P P P T C G A Nucleoside Analog Drugs • Acyclovir: • Chain terminator • Good anti-herpes drug Normal DNA synthesis

13. P P P P P T ACGP-P-P C G A A Nucleoside Analog Drugs • Acyclovir: • Chain terminator Termination • Selective: • Virus phosphorylates drug • Polymerase more sensitive • Also inhibits: • Epstein Barr • Cytomegalovirus

14. Inhibitors of viral reverse transcriptase AZT inhibit virus RT more effectively than normal cellular DNA polymerases not comparable to acyclovir in terms of antiviral specificity the toxicity of AZT in clinical practice

15. mRNA Protein

16. (2) Nonnucleoside reverse transcriptase inhibitors非核苷类反转录抑制物 Nevirapine • It acts by binding directly to reverse transcriptase and disrupting the enzyme‘s catalytic site.

17. (3) Protease inhibitors病毒蛋白酶抑制物 Saquinavir （沙奎那韦） • The first protease inhibitor for HIV • Designed by computer modeling • Inhibit the viral protease Indinavir （茚地那韦） ritonavir（利托那韦）

18. Other type of antiviral agents Amantadine （金刚烷胺） Rimantadine （金刚乙胺） • Synthetic amines specifically inhibit influenza A viruses by blocking viral uncoating

19. B. interferon

20. Interferons • (a) activation of a dsRNA dependent protein kinase to inhibit or stop viral protein synthesis • (b) activation of 2-5 oligo A synthetases  synthesis of 2-5A  activates endonuclease L (itself induced by IFN)  degradation of mRNA  inhibition of protein synthesis • Currently interferons are used in the therapy of chronic HBV hepatitis and HCV hepatitis

21. Viruses Prevention

22. few drugs －－－ useful • vaccines －－－ －important • active immunity • passive immunity

23. Preventive Vaccines • Preparation containing a modified pathogen to induce an immune response to protect against an infectious disease • Given largely to healthy individuals • Among the most powerful tools for disease prevention

24. Vaccination • Relies primarily upon the adaptive immune system

25. Viral Vaccines purpose • The purpose of viral vaccines is to utilize the immune response of the host to prevent viral disease. • poliomyelitis, rubella, measles, and mumps • Vaccination is the most cost-effective method of prevention of serious viral infections.

26. The types of Viral Vaccines • Attenuated Live-Virus Vaccines • Killed- Virus Vaccines • Other Vaccines • Avirulent viral vectors • Purified Component Vaccines • Synthetic Peptides • Naked DNA Vaccines

27. Attenuated Live-Virus Vaccines • Derived from “wild” strains/types • Must replicate to be effective • Mimics natural infection • Circulating antibody may interfere with response

28. Attenuated Live-Virus Vaccines • induce both humoral and cell-mediated immunity • require only one or two immunizations • May revert to a virulent form • formidable safety concerns have limited research on live, attenuated HIV vaccines in humans！！

29. safety considerations • cause AIDS after a long time • revert to the wild-type • cause autoimmune or malignant disease

30. Killed vaccines • Killed vaccines are made by purifying viral preparations to a certain extent and then inactivating viral infectivity in a way that does minimal damage to viral structural proteins.

31. Killed vaccines • Cannot replicate • Minimal interference with circulating antibody • May be adjuvanted • Mostly induce a humoral (antibody) response • May require periodic booster doses

32. Killed vaccines • Relatively safe and easy to produce • Do not cause infection in vaccinee ( with proper manufacturing and controls ). • Immunity may be less complete and shorter lasting than live vaccine/natural infection

34. Combination Vaccines Two or more antigens in a physically mixed preparation for administration as a single immunization • Multi-disease combination • Multi-valent combination

35. Avirulent viral vectors: • The concept is to use recombinant DNA techniques to insert the gene coding for the protein of interest into the genome of an avirulent virus that can be administered as the vaccine. • The prototype vector under study is vaccinia virus.

36. Purified Component Vaccines • Subviral components include in the vaccine only those viral components needed to stimulate protective antibody • obtain the viral proteins by cloning expression, and purifying ; this kind of vaccines containing only the immunizing antigen

37. Recombinant DNA • Single gene (subunit) S-antigen mRNA Hepatitis B vaccine raised in yeast cDNA Express plasmid S-antigen mRNA protein

38. Synthetic Peptides • Viral nucleic acid can be readily sequenced and the amino acid sequence of the gene products predicted. • synthesize short peptides correspond to antigenic determinants on a viral protein.

39. Naked DNA Vaccines • Recombinant DNA techniques are used to create plasmids carrying the genes for the protein of interest. • The plasmids are produced in bacteria, purified, and injected into hosts as a vaccine. • Cells take up the DNA and produce the immunizing protein. • Naked DNA holds the promise of being a simple, cheap, and safe vaccine approach.

40. DNA Vaccines Gene for antigen Muscle cell plasmid Muscle cell expresses protein - antibody made CTL response

41. DNA Vaccines • Possible Problems • Potential integration of plasmid into host genome leading to insertional mutagenesis • Induction of autoimmune responses (e.g. pathogenic anti-DNA antibodies) • Induction of immunologic tolerance (e.g. where the expression of the antigen in the host may lead to specific non-responsiveness to that antigen)

43. Passive immunity • It is provided by the administration of preformed antibody in preparation called immune globulin (Ig). • The immune globulins are useful in the diseases, such as rabies, hepatitis A and B, varicella-zoster and measles.