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)

Suggested Reading:
Introduction to Medicinal Chemistry 3rd Ed. by Patrick
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:
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)

Poliovirus

Hepatitus-B virus

Dengue virus (cause of dengue fever, tropical disease)

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 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., 4th Ed.

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. 4th Ed.

General principles: Viral diseases
DNA-based viruses
Herpes simplex types 1, 2 Varicella zoster Herpes zoster Human papillomavirus Epstein-Barr virus

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

Poxvirus

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

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

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

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)

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)

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”

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)

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)
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
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

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?

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

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

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