Med-Chem 2: Anti-Virals PART 1

Overview: Life Cycle of Viruses

(Attachment →→ Entry → Uncoating → Genome integration → Nucleic acid synthesis → Protein synthesis → Protein maturation → Packaging & assembly →→ Release-multiple copies)

Drugs for CMV:

-Ganciclovir -Valganciclovir -Cidofovir -Foscarnet

Normal process vs In the presence of drug (Nucleoside):

-Lack of hydroxy group in Acyclovir at the bottom (3' OH) results in chain termination. -Presence of hydroxyl group at the top (5' OH) in Acyclovir results in formation of false substrate through phosphorylation

Iceberg concept of viral infection:

-Top (clinical disease) -Bottom (subclinical disease; not enough to see manifestation; asymptomatic)

Anti-HSV drugs summary:

-clovirs -uridines + -Docosanol -Cidofovir + -Foscarnet

Cidofovir has shown efficacy in the treatment of _____1____ resistant herpes and ______2____ resistant CMV.

1. Acyclovir 2. Ganciclovir

1. Valacyclovir is the prodrug of? 2. Valganciclovir is the prodrug of? 3. Famciclovir is the prodrug of?

1. Acyclovir 2. Ganciclovir 3. Penciclovir all are acyclic analogs of deoxyguanosine*

*Study guide Q* 1. Match the following: - Topical, oral or IV - Low bioavailability - Short t1/2 (requires multiple doses) 2. Match the following: - Oral - High bioavailability - Plasma levels 3-5 times greater (less dose frequency)

1. Acyclovir 2. Valacyclovir

Vaccines approved in the US include:

1. Hepatitis A 2. Hepatitis B 3. Influenza A & B 4. Measles 5. Mumps 6. Papilloma 7. Polio 8. Rabies 9. Rotavirus 10. Rubella 11. Varicella 12. Zoster 13. Smallpox 14. Yellow Fever

Ganciclovir & valganciclovir are both useful for HSV infections & CMV. Ganciclovir is administered _____1_____ & as an intraocular implant for CMV retinitis whereas Valganciclovir is administered _____2_____ for end-organ CMV.

1. IV 2. PO

Amantadine & Rimantadine work in the cell due to their ____1______ while Zanamavir & Oseltamivir work on the surface due to their ______2_______.

1. Lipophillicity 2. Hydrophilicity Hydrophilic molecules have limited permeability*

*KNOW* 1. Contains a purine/pyrimidine base + ribose or deoxyribose sugar? 2. Contains a purine/pyrimidine base + ribose or deoxyribose sugar + phosphate group?

1. Nucleoside 2. Nucleotide

*KNOW* _____1_____ is used for genital herpes as a CREAM whereas ____2_____ is used for both genital herpes and herpes zoster virus as an ORAL formulation.

1. Penciclovir 2. Famciclovir

1. Match the following: - Available as inhalation powder - NOT available orally due to polarity & charged guanidine group - Has a much lesser resistance profile 2. Match the following: - Available as oral capsule & suspension - Has widespread use & resistance 3. Match the following: - Available as IV ONLY (too polar) - Contains guanidine group thus less resistance

1. Zanamavir 2. Oseltamivir 3. Peramivir

*Study guide Q* Famciclovir requires 2 activation steps oxidation and deacetylation to convert to penciclovir which then gets ________ phosphates to become the active drug.

3

New anti-influenza drug Xofluza (Baloxavir marboxil) shortened symtoms _________ faster than placebo.

33% •MOA: inhibits the endonuclease activity of the PA •TARGET: Polymerase acidic (PA) protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription.

*EASYGENERATOR Q* Which of the following drugs are called "chain terminators"? *select all that apply* A. Valacyclovir B. Ganciclovir C. Penciclovir D. Cidofovir E. Idoxuridine F. Acyclovir

A & F They lack the 3'OH group on their structure thus cannot elongate = chain termination* All the others contain the 3'OH group*

*EASYGENERATOR Q* Which of the following viruses have RNA genome? *select all that apply* A. HIV B. HBV C. HCV D. Influenza

A, C, D

Which of the following antiviral agents for HSV are DEPENDENT on the initial phosphorylation by viral enzyme?

A. Acyclovir B. Ganciclovir C. Penciclovir D. Trifluridine

Which of the following anti-influenza agents *inhibit viral uncoating*?

A. Amantadine B. Rimantadine

Prodrugs with -OH group masked result in:

A. An increased oral bioavailability B. Better PK and convenient dosing (less pill burden) C. Parent drug hydrolyzation in-vivo

Amantadine & Rimantadine inhibit viral uncoating in host cell by:

A. Blocking the M2 channel B. Stopping the increase of acidic pH Not used anymore due to resistance*

Which of the following antiviral agents are known to *inhibit viral attachment and entry*?

A. Enfuvirtide -- Anti-HIV B. Maraviroc -- Anti-HIV C. Docosanol -- Anti-HSV

*KNOW* Which of the following antiviral agents are useful for both herpes & CMV?

A. Ganciclovir B. Valganciclovir C. Cidofovir D. Foscarnet

*Study guide Q* Which of the following viruses are RNA-based?

A. HIV (HIV-1 & HIV-2) B. Hepatitis A & C C. Influenza Type A, B & C

Cidofovir is used for?

A. HSV infections B. Genital warts C. CMV retinitis Including acyclovir resistant HSV*

Foscarnet is used for:

A. HSV-1 B. HSV-2 C. CMV sometimes can be very good when used in combination with acyclovir or valacyclovir*

*Study guide Q* Which of the following viruses are DNA-based?

A. Herpes virus (HSV-1 & HSV-2) B. Varicella-zoster virus (VZV) C. Cytomegalovirus (CMV) D. Hepatitis B (HBV)

*KNOW; * Which of the following antiviral agents have toxicity implications (too toxic to have systemic effect) and are ONLY available in ophthalmic solutions (topically & locally) for herpes keratitis (HSV-1) ?

A. Idoxuridine B. Trifluridine *Identify structures as too toxic*

Which of the following is TRUE regarding Foscarnet?

A. It mimics pyrophosphate B. It does not require phosphorylation (activation) before attacking viral enzymes C. It can be useful in Acyclovir resistant cases D. Its eliminated by kidneys (renal clearance depends on CrCL)

*KNOW* Which of the following antiviral agents are useful for both HIV & Hepatitis B?

A. Lamivudine B. Tenofovir

Bases (nucleobases) include:

A. Purines B. Pyrimidines Be able to identify the difference between them* Purines have 2 rings fused together whereas pyrimidines only have 1 ring*

Nucleotide analogs mimic deoxyribonucleotides thus are able to compete with normal nucleotides for incorporation into viral genome resulting in:

A. Terminate chain elongation B. Formation of false nucleic acid

Which of the following is TRUE regarding Acyclovir and Valacyclovir?

A. They are excreted renally B. They are used for the treatment of mucocutaneous & genital herpes lesions C. They can be used as prophylaxis therapy in AIDS & other immuno-compromised patients D. They can cause nephrotoxicity, hypotension, delirium & tremors

Ganciclovir and valganciclovir are both associated with:

A. Thrombocytopenia B. Hepatic dysfunction C. Leukopenia D. Neutropenia when combined with other myelosuppressive drugs E. Mucositis

Which of the following is TRUE regarding viruses?

A. Viruses replicate intracellularly and utilize host cell machinery B. All viruses encode proteins that are substantially different from their human counterparts C. Most current antiviral drugs exploit differences between the structures and functions of viral & human proteins to achieve selectivity of antiviral action

Inhibition of neuraminidase prevents cleavage of sialic acid from adjacent hemagglutinin sugars thus preventing release of infectious virus. This occurs with which of the following anti-influenza agents?

A. Zanamavir B. Oseltamivir

*KNOW* The cleavage of sialic acid residues (through sugar cleavage) by neuraminidase facilitates the spread of virus. Which of the following are sialic acid analogues that compete & inhibit neuraminidase thus block sialic acid cleavage from virus & interfere with the spread of infection?

A. Zanamavir B. Oseltamivir Neuraminidase inhibitors*

Which of the following Hepatitis B antiviral agents are available as disopivoxil prodrugs ONLY?

Adefovir & Tenofovir

In the viral life cycle, the start of an infection is signaled by the _______ of virus to the host cell.

Attachment Life cycle begins with the attachment and entry of virion/virus

*EASYGENERATOR Q* Vaccine is NOT available for which of the following infections? A. HAV B. HCV C. Zoster D. Influenza A

B

*EASYGENERATOR Q* Which of the following drugs is responsible for electrolyte abnormalities? A. Acyclovir B. Foscarnet C. Docosanol D. Trifluridine

B

*Study guide Q* Zanamavir & Oseltamivir are anti-influenza agents used for the prophylaxis & treatment of?

Both Influenza type A & B

Which of the following anti-influenza agents *inhibit viral release*?

C. Zanamavir D. Oseltamivir E. Peramivir New drug= Xofluza

Which of the following antiviral agents for HSV is INDEPENDENT of the initial phosphorylation by viral enzyme (through host kinases)?

Cidofovir

*Study guide Q* What is the reservoir form of Cidofovir responsible for its longer intracellular half-life?

Cidofovir-phosphocholine

*Study guide Q* Be able to pinpoint where each of the highlighted virus is located and what type of virus it is (DNA vs RNA) *Correlate viral infection with the site of infection*

Cold sores: docasanol, penciclovir Famciclovir: Shingles, chickenpox, cold sores, STD Acyclovir: systemic, topical, ophthalmic

Cidofovir is __________ to be active.

Diphosphorylated

Which of the following *viral attachment and entry* agents is effective against the herpes virus (HSV)?

Docosanol

Which of the following antiviral agents for HSV does NOT require phosphorylation (activation) before attacking viral enzymes?

Foscarnet

Which of the following antiviral agents is responsible for electrolyte abnormalities?

Foscarnet

*EASYGENERATOR Q* ___________ functional group in Zanamavir makes it active against different flu strains with lesser chances of resistance.

Guanidine

___________ in Zanamavir forms more H-bonds with fairly conserved enzyme active sites (less vulnerable to mutation) and thus results in lesser incidences of resistance.

Guanidine group

Docosanol/Abreva inhibits fusion between ________ envelope and cell membrane.

HSV

*Study guide Q* This viral diseases uses reverse transcription to copy its DNA genome?

Hepatitis B

*KNOW* Interferons (IFNs) are useful for?

Hepatitis B & C

Foscarnet has a structure similar to bisphosphonates thus has a high affinity for bones. This can lead to?

Hypocalcemia Other side effects: nephrotoxicity, CNS effects* can chelate divalent metal ions (Calcium, Magnesium)*

Amantadine & Rimantadine are useful for treatment and prophylaxis of infections due to?

Influenza A virus Effective if given during first 48hrs of symptom onset*

Retroviruses (i.e Hep C, HIV) have additional steps and stages in their life cycles. For example, genome replication of HIV includes the additional step of?

Integration Viral genome is incorporated into the host genome

Analogs of purines and pyrimidines enter the host cells, are phosphorylated by cellular kinases (trapped) resulting in a higher?

Intracellular half-life

Lack of 3'-OH group in Acyclovir triphosphate terminates genome replication by stopping or interfering with what?

NORMAL viral genome replication.

Cidofovir is known to cause major dose-limiting?

Nephrotoxicity

Cidofovir is a polar?

Nucleotide Remember: its independent of initial phosphorylation by viral enzyme b/c it contains a phosphate already → its incorporated into growing DNA chain* TOO polar = available IV, topical & ocular implant*

*KNOW* Which of the following anti-influenza agents is an ester PRODRUG (~70% active drug)?

Oseltamivir KNOW active structure*

Match the following description to the correct agent: -Has a long half life -Requires no dosage adjustment in renal failure -Undergoes hepatic metabolism & results in inactive metabolites excreted in urine

Rimantadine Amantadine does NOT undergo metabolism*

Docosanol/Abreva is a long chain fatty saturated alcohol that can be used for reducing duration of cold sores caused by the herpes simplex virus. A. True B. False

True

Foscarnet has poor oral bioavailability and is therefore only available in IV formulation. A. True B. False

True

Nearly all viruses replicate via attachment, entry, uncoating, gene expression, genome replication, assembly and egress BUT some viruses have additional stages such as maturation. A. True B. False

True

Nucleoside analogs can be called bioprecursors because they have to be phosphorylated to become nucleotide analogues. A. True B. False

True

Valacyclovir is mainly eliminated as acyclovir. A. True B. False

True

Viruses can be DNA based or RNA based. A. True B. False

True

Famciclovir (prodrug) will have a significant oral absorption compared to Penciclovir (used primarily as a cream). A. True B. False

True Famciclovir lacks -OH group thus has better bioavailability*