iPTX3 EX4 L4 (MEDCHEM NON-HIV ANTI-VIRALS) (CAO)

Describe antibody-dependent cell mediated cytotoxicity (ADCC)

Target cell which has been "tagged" by antibodies is recognized and killed by an immune effector cell, most commonly a natural killer (NK) cell

Election of an antiviral agent is based on what four factors (after diagnostic testing is performed)?

1. Overall efficacy

2. Toxicity

3. Patient adherence

4. Cost

3 impacts of drug structure on the therapeutic decision-making process?

1. Dictates the molecular targets available to drug

2. Restricts where that drug can go within the body

3. Determines the length of drug action

Inhibitors of viral attachment, penetration, or early replication? (five)

*1. Amantadine*

*2. Amphotericin B methyl ester*

*3. Interferon/PEG-IFN*

*4. Rimantadine*

5. Tecovirimat

Neuraminidase inhibitors? (four)

*1. Oseltamivir*

2. Peramivir

*3. Zanamivir*

4. Baloxavir marboxil

Fusion inhibitors? (two)

1. Enfuvirtide

2. Maraviroc

Acyclic nucleoside analogues? (eight)

*1. Acyclovir*

2. Adefovir dipivoxil

*3. Cidofovir*

*4. Famciclovir*

*5. Ganciclovir*

*6. Penciclovir*

*7. Valacyclovir*

Conventional nucleoside analogues? (one)

1. Ribavirin

Non-nucleoside analogues? (two)

1. Foscamet

2. Letermovir

Difference in structure between amantadine and rimantadine?

Methyl group

8 types of antiviral agents?

1. Disrupt virus attachment to host cell receptors, penetration, or uncoating

2. Inhibit virus-associated enzymes such as DNA polymerases and others

3. Inhibit viral transcription

4. Inhibit viral translation

5. Interfere with viral regulatory proteins

6. Interfere with glycosylation, phosphorylation, sulfation, etc.

7. Interfere with the assembly of viral proteins

8. Prohibit the release of viruses

Polio virus' receptor?

ICAM-1

HIV virus' receptor?

CD4

Rabies virus' receptor?

Acetylcholine

Vaccinia virus' receptor?

EGF

Epstein-Barr virus' receptor?

CR2/CD21

Herpes virus' receptor?

HVEM

Influenza, reo, coronavirus' receptor?

Sialic acid

SARS, COVID-19 virus' receptor?

ACE2

Human viruses (DNA, not RNA) that involve tumor development? (four)

1. Epstein-Barr Virus (EBV)

2. Certain papillomaviruses

3. Hepatitis B virus (HBV)

4. Kaposi's sarcoma herpesvirus (HHV-8)

Human viruses (RNA, not DNA) that involve tumor development? (two)

1. Human adult T-cell leukemia virus (HTLV-1)

2. Hepatitis virus (HCV)

Two ways tumor viruses can cause carcinogenesis?

1. Introduction of a new "transforming gene" into the cell (direct-acting)

2. Alters the expression of a pre-existing cellular gene or genes (indirect-acting)

How many infected cells per day can ONE cytotoxic T cell (CD8 cell) kill per day?

16 infected cells per day

T/F: Many antiviral drugs are purine or pyrimidine analogs.

True

T/F: Many antiviral drugs are prodrugs, meaning they must be phosphorylated by viral or cellular enzymes to become active molecule.

True

T/F: Anti-viral agents inhibit active replication, so the viral growth is arrested or stopped.

True

Describe the structure of the herpes viruses

Linear, double stranded DNA viruses

Describe herpes-simplex virus 1 (HSV1)

Infections above waist

Gingivostomatitis

Herpes labialis

Encephalitis

Describe herpes-simplex virus 2 (HSV2)

Infections below the waist

Herpes genitalis

Oral agents available for the treatment of herpes virus? (three)

1. Acyclovir

2. Valacyclovir

3. Famciclovir

Topical agents available for the treatment of herpes virus? (three)

1. Acyclovir

2. Docosanol

3. Penciclovir

Ophthalmic agents available for the treatment of herpes virus? (one)

1. Trifluridine

MOA of acyclovir?

Inhibit viral synthesis of DNA

Describe the mechanism by which acyclovir is selectively activated in herpes infected cells

Uptake by infected cell

Phosphorylated by thymidine kinase (TK) to acyclovir monophosphate

Cellular enzymes convert to acyclovir triphosphate

Acyclovir is a __________ inhibitor

A. Competitive

B. Non-competitive

A. Competitive

Competes with deoxyguanosine triphosphate for DNA polymerases

Lacks 3' hydroxyl, so binding to viral DNA poly results in chain termination

Spectrum of activity for acyclovir (three)

1. Herpes simplex 1 & 2

2. Varicella-zoster virus

3. Epstein-Barr virus

T/F: Valacyclovir is an L-valyl ester prodrug of acyclovir.

True

It is rapidly and almost completely converted to acyclovir

Three mechanisms by which resistance to acyclovir has developed?

1. Reduced/absent thymidine kinase

2. Altered TK substrate specificity

3. Alterations in DNA polymerase

T/F: Viruses have yet to show resistance to famciclovir/valacyclovir.

False

Describe the structure of famciclovir

Cyclic adenine analog

Active form of famciclovir?

Penciclovir

Converted to penciclovir in the liver and intestines

Describe the structure of penciclovir

Guanine analog

Treatment options for orolabial herpes (HSV-1)? (two)

1. Penciclovir cream

2. Docosanol

MOA of docosanol?

Interferes with viral fusion to host cell

Treatment option for HSV ocular keratojunctivitis? (one)

1. Trifluridine (Viroptic)

MOA of trifluridine?

Inhibits DNA synthesis

MOA of amphotericin B in viruses?

Same thing pretty much

Binds sterol components that would be incorporated into the virus envelope, reducing their virulence

Also potently inhibits viral replication

Anti-CMV agents? (four)

1. Ganciclovir

2. Valganciclovir

3. Foscarnet

4. Cidofovir

MOA of ganciclovir?

Like acyclovir; competes w/ deoxyguanosine triphosphate -> inhibition of DNA poly

Enzyme responsible (in CMV) for converting ganciclovir to ganciclovir triphosphate?

Viral-encoded phosphotransferase

Spectrum of activity of ganciclovir? (four)

1. CMV (10x potency of acyclovir)

2. EBV (10x potency of acyclovir)

3. HSV/VZV (equal to acyclovir)

4. Very effective in treating CMV retinitis in AIDS patients

Describe the structure of valganciclovir

L-valyl prodrug of ganciclovir

T/F: Valganciclovir is quickly hydrolyzed after absorption.

True

Mechanisms of resistance against valganciclovir? (two)

1. Mutations in the viral protein kinase responsible for monophosphorylation (confers resistance to ganciclovir alone)

2. Mutations in the viral polymerase gene (may show cross resistance to similar antivirals)

T/F: Similar to acyclovir and ganciclovir, activation of foscarnet requires thymidine kinase.

False; thymidine kinase not required.

MOA of foscarnet?

Non-competitive, selective inhibitor at the pyrophosphate binding site on virus-specific DNA polymerase

Does not affect DNA polymerase

T/F: Foscarnet (Foscavir) is available for IV administration only.

True

Spectrum of activity for foscarnet? (three)

1. Ganciclovir resistant strains

2. Acyclovir resistant HSV or VZV

3. EBV

Adverse effects associated with foscarnet? (seven)

1. Renal dysfunction (common, can require dialysis)

2. Anemia

3. CNS disturbances

4. Electrolyte abnormalities

5. Seizures

6. Arrhythmias

7. Neutropenias

Describe the structure of cidofovir

Acyclic nucleoside phosphonate derivative

T/F: Phosphorylation of cidofovir is TK-dependent.

False

MOA of cidofovir

Selective inhibitor of CMV DNA

T/F: HPV types 16 and 18 are associated carcinomas of the cervix, anus, and penis.

True

Viral mechanism of resistance to cidofovir? (one)

1. Point mutations in viral DNA poly in CMV, pox, adenovirus

Confers resistance to ganciclovir in CMV

Foscarnet activity is NOT affected by cidofovir resistance

Antiviral therapy for shingles typically involves (three agents)

Acyclovir, famciclovir, or valacyclovir

Can reduce severity of shingles if administration begins within 72 hours of beginning symptoms

Describe the viral structure of HPV

Non-enveloped double stranded DNA virus

Agents available for the treatment of papilloma? (two bolded)

1. Imiquimod (TLR7 agonist)

2. Trichloroacetic acid (antimitotic and cytotoxic)

MOA of imiquimod

Toll-like receptor 7 agonist that induces cytokines, including interferon-alpha and others.

Indirectly activates APCs including Langerhans and T-helper cells

Spectrum of activity for imiquimod

External and perianal genital warts caused by HPV

T/F: Trichloroacetic acid (Tri-Chlor) is a keratolytic agent.

True

Two varieties of spikes found on influenza viruses?

1. Neuraminidase

2. Hemagglutinin

T/F: Influenza virus undergoes antigenic shifts/drifts.

True

Agents for the treatment of influenza? (four)

1. Oseltamivir

2. Zanamivir

3. Amantadine

4. Rimantadine

Describe the role of hemagglutinin (HA)

Lectin which mediates binding of the virus to target cells and entry of the viral genome into the target cell

Describe the role of neuraminidase (NA)

Involved in the release of viral progeny from infected cells by cleaving sugars that bind the mature viral particles

MOA of oseltamivir

Oral neuraminidase inhibitor

Cleaves terminal sialic acid residues on glyoconjugates and destroys receptors

Newly formed virions adhere to cell surface + limit spread

Spectrum of activity for oseltamivir? (three)

Inflenza A/B

Avian influenza

H5N1 disease

How is zanamivir (Relenza) administered?

Via inhalation

MOA of amantadine/rimantadine?

Prevents the release of viral nucleic acid into host cell

Blocks M2 protein channel (type A only)

Disrupts H transport, viral uncoating in host cell and therefore viral RNA transcription

Adverse effects associated with amantadine/rimantadine? (five)

1. Seizures

2. Anticholinergic

3. CNS

4. Edema

5. Blurry vision

T/F: The use of amantadine/rimantadine for their antiviral properties is not currently recommended in the US.

True

MOA of paxlovid

Nirmatrelvir: Oral protease inhibitor which inhibits a key enzyme that the COVID virus requires in order to make functional virus particles

Ritonavir: Used to boost levels of nirmatrelvir

T/F: Ritonavir is a strong CYP3A4 inhibitor.

True

Describe monkeypox

Viral zoonosis and the symptoms are like smallpox

Describe the viral structure of monkeypox

Enveloped, double-stranded DNA virus

Which of the following monkeypox strains has a greater mortality rate and is more transmissible?

A. Central African

B. West African

A. Central African

Treatment option for monkeypox?

Tecovirimat (TPOXX or ST-246) - used traditionally in smallpox, but can be used in monkeypox.

Limited in at-risk for severe disease patients (i.e. immunocompromised, children)

Two available smallpox vaccines that can be used to protect against monkeypox?

ACAM2000

JYNNEOS