Exam 4: Antivirals I Flashcards
What kind of virus is herpes?
Large, double-stranded DNA virus
The varicella zoster virus (VZV) can cause what 2 conditions?
Chickenpox
Shingles (reactivation)
What is a potential complication of shingles?
Postherpetic neuralgia (PHN)
Who should receive Shingrix to prevent from shingles and how many doses?
2 doses
In all immunocompetent adults 50 and older
Who typically gets infected by cytomegalovirus?
Immunocompromised people
What is a potential complication of cytomegalovirus?
Cytomegalovirus-retinitis
What are all of the potential anti-herpes agents?
Acyclovir
Valacyclovir
Cidofovir
Pencyclovir
Ganciclovir
Valganciclovir
Foscarnet
The anti-herpesvirus agents are all what (structurally)?
Nucleotide analogs
Prodrugs, must be phosphorylated
(chain-terminator) -block DNA replication by blocking phosphodiester bonds
What is the structure of acyclovir?
Acyclic guanosine derivative
What is a benefit to using acyclovir for herpes therapy?
it selectively accumulates in infected cells
-low toxicity
How does acyclovir become active?
Requires 3 phosphorylation events:
-Viral Thymidine Kinase
(1st step, where toxicity comes from)
-Cellular GMP Kinase (HOST KINASE)
-Cellular Kinase (HOST KINASE)
What step in acyclovir activation causes toxicity?
1st phosphorylation by viral thymidine kinase
What is an important thing to note with acyclovir activation?
The last 2 phosphorylations are done by host kinases
Why is acyclovir selective for viral cells?
The first phosphorylation step in its activation can only be done by a viral kinase
What is the MOA of acyclovir?
Competitive inhibitor of viral DNA polymerase
(Competes with dGTP)
Note that competition occurs at a lower concentration for viral DNA pol than host, which decreases the risk for toxicity
This binds the DNA polymerase to the template irreversible
Acyclovir becomes incorporated into DNA
overall action: CHAIN TERMINATOR
-blocks ability to create the next phosphodiester bond (lacks necessary hydroxyl group)
What viruses does acyclovir have activity against?
HSV-1
HSV-2
VZV (varicella)
What are the 2 ways that resistance to acyclovir can develop?
Mutations in viral thymidine kinase
(responsible for first phosphorylation)
Mutations in viral DNA polymerase
(drug is not accommodated as well, not able to inhibit the polymerase as well)
who is more likely to experience resistance to acyclovir?
Immunocompromised people
What is the structure of valacyclovir?
L-valyl ester of acyclovir
What happens to valacyclovir when it enters the body?
It is rapidly converted to acyclovir by esterases in the intestine and liver
-Transported by INTESTINAL amino acid transporters
(does not cross membrane as well as acyclovir)
*oral drug
How does the efficacy of valacyclovir compare to acyclovir?
Valacyclovir is more efficacious for all indications
How does the MOA of Famciclovir and Penciclovir differ from Acyclovir and Valacyclovir?
DO NOT CAUSE IMMEDIATE CHAIN TERMINATION
True or False: Viral kinase mutants show cross-resistance to both penciclovir and acyclovir
True
-resistance to one means resistance to the other
How does the MOA penciclovir differ from acyclovir?
Penciclovir has a higher affinity for HSV TK than acyclovir
-this means that penciclovir is able to bind better
-levels of penciclovir triphosphate in infected cells are much higher than those of acyclovir triphosphate
*Note that HSV DNA polymerases have a higher affinity for acyclovir giving the 2 drugs similar efficacy
What are the clinical uses of oral famciclovir?
Primary + Recurrent Genital Herpes
Acute herpes zoster
What are the clinical uses of topical penciclovir?
Recurrent herpes labialis
Ganciclovir has a similar structure and the same MOA as what other drug?
Penciclovir
Ganciclovir is better used for what indication than the other drugs listed?
Better substrate for cytomegalovirus kinase
What drug + dosage form is used to treat CMV retinitis?
Ganciclovir
IV, oral, and intraocular implants
what drug + dosage form is used for CMV prophylaxis?
Ganciclovir
Oral
How does the toxicity of ganciclovir compare to acyclovir?
Toxicity is more severe
What toxicity is associated with ganciclovir?
Myelosuppression
How does resistance to Ganciclovir occur?
Mutations in:
CMV kinase
CMV DNA pol
note that there is no cross-resistance with other drugs
What is the structure of Valganciclovir?
Monovalyl ester of ganciclovir
*converted to ganciclovir in intestine and liver
What is the benefit of Valganciclovir over Ganciclovir?
Increased bioavailability
What is the indication of Valganciclovir?
CMV retinitis in AIDS patients
What is the structure of Foscarnet?
Inorganic pyrophosphate compound
What is the MOA of Foscarnet?
Inhibits viral DNA polymerase
-Blocks pyrophosphate binding site of the viral DNA polymerase
-Inhibits cleavage of pyrophosphate from dNTPs
-DNA is ultimately unable to translocate
How does Foscarnet differ from the other herpes virus drugs?
Does not require phosphorylation for activity
How is foscarnet administered?
IV only
(poor oral bioavailability)
Foscarnet is synergistic with which other drug?
Ganciclovir
How can resistance occur against Foscarnet?
Mutations in DNA pol or HIV RT
Foscarnet shows cross-resistance with what drug?
Ganciclovir
Foscarnet does not have cross-resistance with what drug?
Cidofovir
What is the structure of Cidofovir?
Acyclic nucleoside phosphonate analog of cytosine
How does the action of cidofovir differ from other drugs?
It only requires 2 phosphorylations by the cellular kinases
Is not virally phosphorylated
What is the activity of cidofovir?
Broad spectrum
(covers many viruses)
What is the MOA of cidofovir?
Competitive inhibitor and chain terminator
What is the indication of cidofovir?
CMV retinitis
What is the moa of Letermovir?
Newest anti-herpes drug
Non-nucleoside inhibitor (does not have a nucleotide analog structure)
Binds the CMV terminase complex
*Prevents cleavage and packaging
*No effect on protein synthesis or DNA replication
True or False: Letermovir has no cross resistance with other drugs
True
What kind of virus is Influenza?
Negative stranded RNA virus
What are the types of influenza?
A
B
C
Who does Influenza virus A infect?
Humans + Animals
Who does Influenza virus B affect?
Humans only
What is the main characteristic of Influenza virus C?
Mild/undetectable
Vaccines protect against what type(s) of influenza?
A + B
What are the 2 subtypes of Influenza A?
Hemagglutinin (H1-H16)
Neuraminidase (N1-N9)
How does the influenza virus spread?
It takes part of the plasma membrane from the host to create new viral particles
Which part of the influenza virion is critical for viral release from the cell so it can spread/replicate?
NA (neuraminidase)
What drugs are neuraminidase inhibitors?
Oseltamivir
Zanamavir
Baloxavir
Peramivir
How is oseltamivir activated?
Liver esterases
(note that this is a prodrug)
Oseltamivir is active against which forms of influenza?
A and B
(more A)
What is a limitation to oseltamivir use?
It must be initiated within 48 hours of first symptoms to be useful
Resistance develops more easily against which drug: Oseltamivir or Zanamivir
Oseltamivir
(more floppy drug)
Zanamivir can be used for what kinds of influenza?
A and B
What is a unique thing to remember about Zanamivir?
It is an oral inhaler
What is an important side effect of Zanamavir?
Bronchospasm
Who should not receive Zanamavir?
Patients with airway diseases like asthma and obstructive pulmonary disease
What is the structure or Peramivir?
Transition state analog of sialic acid
What is the indication of Peramivir
Influenza A + B
What is the dosage form of Peramivir?
IV or Injectable
Who should receive Peramivir?
Adult patients able to receive IV and based on one or more of the following reasons:
-Patient not responding to oral or inhaled therapy
-No other route is expected to be dependable/feasible
-Clinician judgement
What is the mechanism of Baloxavir?
Inhibits viral cap-snatching (blocks transcription)
What is the indication of Baloxavir?
Influenza within 48 hrs of symptoms
-age 12+ only
What are the side effects of Baloxavir?
Diarrhea
Bronchitis
What kind of virus is Hepatitis C?
Small, positive-stranded RNA
How is Hepatitis C transmitted?
Blood
How do interferons fight viral infections?
Induce synthesis of cellular proteins
How do ribonucleases fight viral infections?
Degrade viral RNA but not cellular RNA
What is the indication for Interferon alpha (drug)?
Hepatitis C
Hepatitis B
Human herpes virus
Papillomavirus
Interferon alpha should be combined with which drug to improve efficacy?
Ribavirin
what are the Hepatitis C Virus inhibitor drugs?
Ribavirin
Grazoprevir
Voxilaprevir
Glecaprevir
Sofosbuvir
Ledipasvir
Elbasvir
Dasabuvir
Daclatasvir
Velpatasvir
Pibrentasvir
How is ribavirin activated?
Phosphorylated by cellular kinases to triphosphate form
(Prodrug)
What is the MOA of Ribavirin?
Inhibits Inosine monophosphate dehydrogenase (IMPDH)
-reduces GTP levels
Directly inhibits viral RNA polymerase
-Incorporation into viral RNA leads to an error catastrophe
What are the uses for Ribavirin?
Combination therapy for Hep C
Aerosol can be used for RSV pneumonia in children
How do HCV protease inhibitors work?
Mimic substrate structure and locks the protease from being active
-this prevents the protease from cleaving its substrate
What drugs act as P2-P4 substrate analog HCV protease inhibitors?
Grazopevir
Voxilaprevir
Glecaprevir
What are the advantages of using HCV protease inhibitors?
Once daily dosing
Well tolerated
How do mutations against HCV protease inhibitors occur?
Mutations in NS3 active site
HCV RNA polymerase inhibitors block what?
NS5B (HCV RNA polymerase)
What drug is a HCV RNA polymerase inhibitor?
Sofosbuvir
How is Sofosbuvir activated?
Converted to monophosphate by liver enzymes
Triphosphorylated by nucleotide kinases
How does Sofosbuvir work?
Incorporated into viral RNA chain of HCV
Causes chain termination
Which drug is a non-nucleoside RNA polymerase inhibitor?
Dasabuvir
Dasabuvir is not active against what?
HCV genotype 2, 3, 4
What is the MOA of Dasabuvir?
Binds to pal I site of HCV RNA polymerase
Prevents conformational changes
Blocks nucleotide incorporation into viral RNA
What are the HCV NS5A inhibitors?
Ledipasvir
Elbasvir
Daclatasvir
Velpatasvir
Pibrentasvir
What is the role of NS5A?
Required for HCV RNA replication
What is the MOA of the HCV NS5A inhibitors?
Inhibit both viral RNA replication and assembly/release of infectious particles
For HCV inhibitors, the ending -previr indicates what?
HCV NS3 protease inhibitor
For HCV inhibitors, the ending -asvir indicates what?
HCV NS5A inhibitor
For HCV inhibitors, the ending -buvir indicates what?
HCV NS5B inhibitor
What black box warning is associated with HCV direct acting antivirals?
Hepatitis B Virus reactivation
What kind of virus is Hepatitis B?
Partially double-stranded DNA virus
-genome includes an RNA intermediate that is converted to viral DNA by reverse transcriptase
What are the anti-HBV drugs?
Tenofovir
Lamivudine
Entecavir
What are the important points about tenofovir?
-Prodrug
-Only needs 2 phosphorylations
What 3 drugs are used for COVID?
Remdesivir
Nirmatrelvir
Molnupiravir
What are the important points about Remdesivir?
Prodrug
IV
Approved for COVID
What are the important points about Nirmatrelvir?
Inhibitor of SARS-CoC-2 3C-like protease (3CL^pro)
Mild-moderate covid
Use within 5 days of symptom onset
Peptidomimetic inhibits active site of 3CL^pro
*Use ritonavir to boost levels
What are the important points about Molnupiravir?
Prodrug
For mild-moderate COVID
Mutagenic potential
