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 Poliovirus

disease virus rhinovirus
(infects cattle, (“common cold”)
pigs)

Hepatitus-B Dengue virus Human

virus (cause of papillomavirus
dengue fever,
tropical disease)

Paramecium bursaria
http://www.cgl.ucsf.edu/Research/virus/capsids/viruses.html 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 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 Resultant disease

HIV-1, HIV-2 HIV; AIDS
Rhinovirus respiratory/GI infections
(“common cold”)
Hepatitis A, B, C viruses Hepatitis
Influenza 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 Æ 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