Structure of viruses Categories of viruses: DNA and RNA-based Examples of viral diseases General anti-viral approaches

Transcription

1 Anti-viral drugs General background Structure of viruses Categories of viruses: DNA and RNA-based Examples of viral diseases General anti-viral approaches Example 1: Targeting early stages of viral infection Example 2: Specifically targeting DNA viruses (e.g. HSV) Example 3: Specifically targeting RNA viruses (e.g. HIV)

2 Suggested Reading: Introduction to Medicinal Chemistry 3 rd Ed. by Patrick Chapter 17 General information on (concepts): virus capsid retrovirus (viral drug targets): herpes simplex virus influenza HIV (anti-viral drugs): amantadine ; interferon ; acyclovir ; azt ; indinavir ; etc.

3 General principles Viruses are parasitic, i.e. they utilize: Host metabolic enzymes Host ribosome for protein synthesis Structure of viruses Nucleic acid core: DNA or RNA Often contain crucial virus-specific enzymes Surrounded by protein: capsid and sometimes an outer lipid envelope Complete viral particle: virion Often visible by electron microscopy: HIV-1 Hepatitis B virus Human papillomavirus

4 General principles: Capsids Computer-generated examples of self-assembled capsid structures: Foot and mouth disease virus (infects cattle, pigs) Human rhinovirus ( common cold ) Poliovirus Hepatitus-B virus Dengue virus (cause of dengue fever, tropical disease) Human papillomavirus Paramecium bursaria chlorellavirus (infects green algae)

5 General principles: DNA viruses Based on viral genomic dsdna Life cycle of a generic DNA virus: Virion often contains specialized enzymes: viral DNA/RNA polymerases etc. Molecular Biology of the Cell Alberts et al., B., 4 th Ed.

6 General principles: RNA viruses Based on viral genomic ssrna Example, life cycle of HIV-1: HIV virion contains enzymes: reverse transcriptase integrases proteases But note: not all RNA viruses are retroviruses! (e.g. influenza) Molecular Cell Biology, Lodish et al. 4 th Ed.

7 General principles: Viral diseases DNA-based viruses Resultant disease Herpes simplex types 1, 2 herpes (skin); encephalitis (brain) Varicella zoster chickenpox (children) Herpes zoster shingles (adult) Human papillomavirus warts (plantar, genital), cancer Epstein-Barr virus Mononucleosis ( mono ); Burkitt s lymphoma; nasopharyngeal carcinoma Poxvirus smallpox; chickenpox RNA-based viruses HIV-1, HIV-2 Rhinovirus Hepatitis A, B, C viruses Influenza A, B, C viruses Resultant disease HIV; AIDS respiratory/gi infections ( common cold ) Hepatitis Influenza A, B, C

8 Approaches to treat viral diseases As viruses are intracellular parasites (utilizing host machinery), there are very few unique targets in viruses This distinguishes viruses from other infectious organisms: (Bacteria, protozoa, fungi) Challenges in designing anti-viral treatments: Host cell must be immune to treatment! (to limit off-target toxicity) Viral infection disease symptoms often associated with latency period General anti-viral strategies are to inhibit: Viral attachment to host cell, penetration, and uncoating Viral enzymes: DNA/RNA polymerases, etc Reverse transcriptases, proteases, etc. Host expression of viral proteins Assembly of viral proteins Release of virus from cell surface membranes

9 Example 1: Targeting early stages of viral infection Overview Drug approaches that target the uncoating of the influenza viral particle Amantadine HCl Rimantidine HCl Interferon: Signal-transducing proteins that interfere with viral protein expression

10 Example 1: Targeting early stages of viral infection Amantadine HCl Approved by FDA in 1976 to treat influenza A (not influenza B) Mechanism: Inhibits the un-coating of the viral genome Specifically targets a protein called M2 (an ion channel) Inactive against influenza B, which lacks M2 Pharmacokinetics: Well absorbed orally; crosses BBB 90% excreted unchanged ; no reports of metabolic products Side effects: Low toxicity at therapeutic levels; some CNS side effects (scary hallucinations)

11 Example 1: Targeting early stages of viral infection Rimantadine HCl Approved by FDA in 1994 to treat influenza A (not influenza B) Mechanism / Pharmacokinetics Similar to amantadine (same target: M2 ion channel protein) Side effects: Fewer CNS effects than amantadine (i.e., better hallucinations)

12 Example 1: Targeting early stages of viral infection Interferon What is interferon? Discovered in 1957 Proteins produced naturally by cells in immune system after exposure to viruses May be a natural anti-viral factor General classes of interferon: Alpha, beta, gamma secreted from different types of cells Pharmaceutical use: Not practical as a pharmaceutical until mass recombinant production (~1980s) Still considered a drug of the future

13 Example 1: Targeting early stages of viral infection Interferon has broad spectrum anti-viral activity (DNA viruses): herpes simplex 1 and 2; herpes zoster human papillomavirus (genital warts) (RNA viruses): influenza; chronic hepatitis; common cold (also): breast cancer; lung cancer; Karposi s sarcoma (cancer associated with AIDS) Pharmacokinetics: Not orally bioavailable Typically routes: intramuscular, subcutaneous, topical (nasal spray)

14 Example 1: Targeting early stages of viral infection Interferon, mechanism of action: 1) binds to cell surface receptors 2) induces expression of translation inhibitory protein (TIP) 3) TIP binds to ribosome, inhibits host expression of viral proteins

15 Example 2: Specifically Targeting DNA viruses (HSV) Background on Herpes simplex virus (HSV) Cause of several painful skin/eye infections The two most common types: HSV-1: orofacial (cold sores on the mouth and lips) HSV-2: genital herpes Both types: can have dormancy periods (often for several year periods) are infectious, but the potential is greatest during an outbreak currently incurable but generally not fatal Neonatal HSV (transmission from mother to child) rare (< ~3.61 / 1,000,000) but commonly fatal to the child (25% of the time) Prevalence in HSV United States: HSV-1: 50 million HSV-2: 40 million Two nucleoside-mimic HSV drugs will be discussed: acyclovir (purine mimic) idoxuridine (pyrimidine mimic)

16 Example 2: Specifically Targeting DNA viruses (HSV) Acyclovir A drug primarily used to treat herpes infections (HSV-1, HSV-2) This can be thought of as a purine mimic! Note similarity to 2 -deoxyguanosine: lack of 3 -hydroxyl (!!) Administration: topical ointment, intravenous, oral

17 Example 2: Specifically Targeting DNA viruses (HSV) Acyclovir: Mechanism of action Step 1: activation so will normal (non-infected) cells be sensitive to this drug?

18 Example 2: Specifically Targeting DNA viruses (HSV) Acyclovir: Mechanism of action Step 2: incorporation into growing DNA chain

19 Example 2: Specifically Targeting DNA viruses (HSV) Acyclovir: Pharmacokinetics Fairly poor oral absorption (15-30%) Improved by design of suitable prodrugs:

20 Example 2: Specifically Targeting DNA viruses (HSV) Idoxuridine Also used to treat herpes infections (HSV-1, HSV-2, VZV) This is a pyrimidine nucleoside mimic! Note similarity to 2-deoxythymidine: with interesting iodouridine base

21 Example 2: Specifically Targeting DNA viruses (HSV) Idoxuridine: Mechanism of action Step 1: activation Less selectivity between HSV-infected and non-infected cells

22 Example 2: Specifically Targeting DNA viruses (HSV) Idoxuridine: Mechanism of action Step 2: incorporation into growing DNA chain