Antiviral 1

Anti-viral drugs „

General background „ „ „ „

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

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Example 1: Targeting early stages of viral infection

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Example 2: Specifically targeting DNA viruses (e.g. HSV)

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Example 3: Specifically targeting RNA viruses (e.g. HIV)

Suggested Reading: „

Introduction to Medicinal Chemistry 3rd Ed. by Patrick „

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Chapter 17

General information on http://en.wikipedia.org (concepts): „ “virus” „ “capsid” „ “retrovirus” (viral drug targets): „ “herpes simplex virus” „ “influenza” „ “HIV” (anti-viral drugs): „ “amantadine”; “interferon”; “acyclovir”; “azt”; “indinavir”; etc.

General principles „

Viruses are parasitic, i.e. they utilize: „ „

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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

General principles: Capsids „

Computer-generated examples of self-assembled capsid structures:

Foot and mouth Human disease virus rhinovirus (infects cattle, (“common cold”) pigs)

Hepatitus-B virus

Dengue virus (cause of dengue fever, tropical disease)

Poliovirus

Human papillomavirus

http://www.cgl.ucsf.edu/Research/virus/capsids/viruses.html

Paramecium bursaria chlorellavirus (infects green algae)

General principles: DNA viruses „

Based on viral genomic dsDNA

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Life cycle of a generic DNA virus:

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Virion often contains specialized enzymes: „ „

viral DNA/RNA polymerases etc.

Molecular Biology of the Cell Alberts et al., B., 4th Ed.

General principles: RNA viruses „

Based on viral genomic ssRNA

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Example, life cycle of HIV-1:

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HIV virion contains enzymes: „ „ „

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reverse transcriptase integrases proteases

But note: not all RNA viruses are retroviruses! (e.g. influenza)

Molecular Cell Biology, Lodish et al. 4th Ed.

General principles: Viral diseases DNA-based viruses

Resultant disease

Herpes simplex types 1, 2 Varicella zoster Herpes zoster Human papillomavirus Epstein-Barr virus

Poxvirus

herpes (skin); encephalitis (brain) chickenpox (children) shingles (adult) warts (plantar, genital), cancer Mononucleosis (“mono”); Burkitt’s lymphoma; nasopharyngeal carcinoma smallpox; chickenpox

RNA-based viruses

Resultant disease

HIV-1, HIV-2 Rhinovirus

HIV; AIDS respiratory/GI infections (“common cold”) Hepatitis Influenza A, B, C

Hepatitis A, B, C viruses Influenza A, B, C viruses

Approaches to treat viral diseases „

As viruses are intracellular parasites (utilizing host machinery), there are very few unique targets in viruses „

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Challenges in designing anti-viral treatments: „ „

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This distinguishes viruses from other infectious organisms: (Bacteria, protozoa, fungi) Host cell must be immune to treatment! (to limit off-target toxicity) Viral infection Æ disease symptoms often associated with latency period

General anti-viral strategies are to inhibit: „ „

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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

Example 1: Targeting early stages of viral infection Overview „ Drug approaches that target the uncoating of the influenza viral particle „ „

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Amantadine HCl Rimantidine HCl

Interferon: „

Signal-transducing proteins that interfere with viral protein expression

Example 1: Targeting early stages of viral infection „

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Amantadine HCl

Approved by FDA in 1976 to treat influenza A (not influenza B) Mechanism: „ „ „

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Pharmacokinetics: „ „

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Inhibits the un-coating of the viral genome Specifically targets a protein called M2 (an ion channel) Inactive against influenza B, which lacks M2 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)

Example 1: Targeting early stages of viral infection „

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Rimantadine HCl

Approved by FDA in 1994 to treat influenza A (not influenza B) Mechanism / Pharmacokinetics „

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Similar to amantadine (same target: M2 ion channel protein)

Side effects: „

Fewer CNS effects than amantadine (i.e., better hallucinations)

Example 1: Targeting early stages of viral infection „

Interferon

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What is interferon? „ „

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General classes of interferon: „ „

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Discovered in 1957 Proteins produced naturally by cells in immune system after exposure to viruses May be a “natural anti-viral factor”

Alpha, beta, gamma secreted from different types of cells

Pharmaceutical use: „

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Not practical as a pharmaceutical until mass recombinant production (~1980s) Still considered a “drug of the future”

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)

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Pharmacokinetics: „ „

Not orally bioavailable Typically routes: intramuscular, subcutaneous, topical (nasal spray)

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

Example 2: Specifically Targeting DNA viruses (HSV) „

Background on Herpes simplex virus (HSV) „ „

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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)

Example 2: Specifically Targeting DNA viruses (HSV) „

Acyclovir

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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 (!!)

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Administration: topical ointment, intravenous, oral

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Example 2: Specifically Targeting DNA viruses (HSV) „

Acyclovir: Mechanism of action „

Step 1: activation

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…so will “normal” (non-infected) cells be sensitive to this drug?

Example 2: Specifically Targeting DNA viruses (HSV) „

Acyclovir: Mechanism of action „

Step 2: incorporation into growing DNA chain

Example 2: Specifically Targeting DNA viruses (HSV) „

Acyclovir: Pharmacokinetics „ „

Fairly poor oral absorption (15-30%) Improved by design of suitable prodrugs:

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

Example 2: Specifically Targeting DNA viruses (HSV) „

Idoxuridine: Mechanism of action „

Step 1: activation

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Less selectivity between HSV-infected and non-infected cells

Example 2: Specifically Targeting DNA viruses (HSV) „

Idoxuridine: Mechanism of action „

Step 2: incorporation into growing DNA chain