Anti-viral drugs

General backgroundStructure of virusesCategories of viruses: DNA and RNA-basedExamples of viral diseasesGeneral 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 PatrickChapter 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 principlesViruses are parasitic, i.e. they utilize:

Host metabolic enzymesHost ribosome for protein synthesis

Structure of virusesNucleic acid core: DNA or RNAOften contain crucial virus-specific enzymesSurrounded 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: CapsidsComputer-generated examples of self-assembled capsid structures:

Dengue virus(cause of

dengue fever,tropical disease)

Foot and mouth disease virus

(infects cattle, pigs)

Human rhinovirus

(“common cold”)

Poliovirus

Human papillomavirus

Hepatitus-B virus

Paramecium bursariachlorellavirus (infects green algae)http://www.cgl.ucsf.edu/Research/virus/capsids/viruses.html

General principles: DNA viruses

Based on viral genomic dsDNA

Life cycle of a generic DNA virus:

Virion often contains specialized enzymes:

viral DNA/RNA polymerasesetc.

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 transcriptaseintegrasesproteases

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

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

General principles: Viral diseasesDNA-based viruses Resultant diseaseHerpes simplex types 1, 2 herpes (skin); encephalitis (brain)Varicella zoster chickenpox (children)Herpes zoster shingles (adult)Human papillomavirus warts (plantar, genital), cancerEpstein-Barr virus Mononucleosis (“mono”);

Burkitt’s lymphoma;nasopharyngeal carcinoma

Poxvirus smallpox; chickenpox

RNA-based viruses Resultant diseaseHIV-1, HIV-2 HIV; AIDSRhinovirus respiratory/GI infections

(“common cold”)Hepatitis A, B, C viruses HepatitisInfluenza A, B, C viruses 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 latencyperiod

General anti-viral strategies are to inhibit: Viral attachment to host cell, penetration, and uncoatingViral enzymes:

DNA/RNA polymerases, etcReverse transcriptases, proteases, etc.

Host expression of viral proteinsAssembly of viral proteinsRelease of virus from cell surface membranes

Example 1: Targeting early stages of viral infection

OverviewDrug approaches that target the uncoating of the influenza viral particle

Amantadine HClRimantidine 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 genomeSpecifically targets a protein called M2 (an ion channel)Inactive against influenza B, which lacks M2

Pharmacokinetics: Well absorbed orally; crosses BBB90% excreted unchanged ; no reports of metabolic products

Side effects:Low toxicity at therapeutic levels; some CNS side effects (scaryhallucinations)

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

InterferonWhat is interferon?

Discovered in 1957 Proteins produced naturally by cells in immune system after exposure to virusesMay 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 zosterhuman 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 bioavailableTypically routes: intramuscular, subcutaneous, topical (nasal spray)

Example 1: Targeting early stages of viral infection

Interferon, mechanism of action:1) binds to cell surface receptors2) 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 infectionsThe 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 outbreakcurrently 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)

AcyclovirA 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 actionStep 1: activation

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

Example 2: Specifically Targeting DNA viruses (HSV)

Acyclovir: Mechanism of actionStep 2: incorporation into growing DNA chain

Example 2: Specifically Targeting DNA viruses (HSV)

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

Example 2: Specifically Targeting DNA viruses (HSV)

IdoxuridineAlso 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 actionStep 1: activation

Less selectivity between HSV-infected and non-infected cells

Example 2: Specifically Targeting DNA viruses (HSV)

Idoxuridine: Mechanism of actionStep 2: incorporation into growing DNA chain