Valganciclovir - Monovalyl ester of ganciclovir - ___ bioavailability (60%) - Rapidly hydrolyzed to ___ by esterases in intestine and liver - Used to treat CMV ___ in ___ patients

- increases - ganciclovir - retinitis, AIDS

Foscarnet - Inorganic pyrophosphate compound (phosphonoformic acid) - Inhibits viral ___ , RNA polymerase, and HIV RT - does NOT require ___ - Blocks ___ binding site of the viral DNA polymerase - Inhibits cleavage of pyrophosphate from dNTPs MOA - Carboxyl overlaps with binding site B-phosphate - Phosphonates occupies position of g-phosphate - Traps polymerase in ___ formation - DNA is unable to ___

- DNA polymerase - phosphorylation - pyrophosphate - closed - translocate

Antivirals 1 Flashcards by Reagan Smith

Herpes

large dsDNA
enveloped
Can cause latent infections

HSV-1
- Commonly causes ___ herpes, but can cause genital herpes
- ~60 % of adults in US are seropositive

HSV-2
- Commonly causes ___ herpes, but can cause oral herpes

oral
genital

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VZV (varicella zoster virus)

Causes ___ after primary infection
Can reactivate later in life

Shingles
- Viruses migrates to ___ in area of infection
transmission
- shingles isnt transmitted, but virus can cause chicken pox

chickenpox
ganglia

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CMV (cytomegalovirus)

Severe disease can occur if
- Infection occurs during ___ development
- Infection occurs in ___ people

fetal
immunocompromised

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Anti-herpesvirus agents - Acyclovir

___ ___ derivative
- Lacks ___
- Selectively accumulates in ___ cells
- requires ___ phosphorylation events

MOA: ___ inhibitor of viral DNA polymerase
- DNA polymerase becomes bound to ___
- Acts as chain ___

Acyclic guanosine
3’ hydroxyl
infected
3
competetive
irreversibly
terminator

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Anti-herpesvirus agents - Acyclovir

SoA: ___ , ___ , and ___
- not great for CMV

Bioavailaility: 15-30%, not affected by food

AE: well tolerated, maybe N, D, rash, headache and very rarely, renal insufficiency or neurotoxicity have been reported

Resistance
- Mutations in viral ___ (most common).
- mutations in viral ___
- emerges more frequently in immunocompromised people

HSV-1, HSV-2 and VZV
thymidine kinase
DNA polymerase

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Anti-herpesvirus agents - valacyclovir

___ ester of acyclovir
Rapidly converted to acyclovir by esterases in the intestine and liver
transported by ___ amino
acid transporters
Bioavailability is 48 to 54 %
___ efficacy compared to acyclovir for all indications

L-valyl
intestinal
improved

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Famciclovir and penciclovir

Famciclovir is a ___ of penciclovir
converted by first pass metabolism in intestin and liver

MOA
- Activated by viral and cellular kinases
- ___ inhibitor of viral DNA polymerase
- Does NOT cause immediate chain termination - allows for short chain ___

Viral ___ mutants confer cross-resistance to penciclovir and acyclovir

prodrug
competetive
elongation
kinase

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Penciclovir versus Acyclovir

Penciclovir has a ___ affinity for HSV ___ than acyclovir
- levels higher in infected cells
- more stable
- Intracellular half-life is 10- to 20-fold longer for ___

HSV DNA ___ have a higher affinity for acyclovir triphosphate than for penciclovir triphosphate
- Net effect: both drugs have similar antiviral potencies

Acyclovir triphosphate is an obligate DNA
chain ___

Penciclovir triphosphate allows limited DNA chain ___ (short-chain terminator)
- 3’ hydroxyl group on its acyclic side chain

higher, TK
Penciclovir triphosphate
polymerases
terminator
elongation

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Clinical uses of famciclovir and penciclovir

Oral famciclovir
- Primary and recurrent ___ herpes
- Acute herpes ___

Topical penciclovir
- Recurrent herpes ___

70 % bioavailable

genital
zoster
labialis

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Ganciclovir

Structurally very similar to penciclovir
MOA: same as ___
Better substrate for ____ kinase than acyclovir (100x more active)
Intracellular half-life 12 h

Poor bioavailability (6 - 9 %)

Clinical uses:
- IV, oral and intraocular implants can be used to treat CMV ___
- Oral ganciclovir can be used for CMV ___

Toxicity more ___ than acyclovir
- ___
- neutropenia
- thrombocytopenia

Resistance
- mutations in ___ kinase (UL97 gene)
- mutations in CMV ___ (UL54)
- Mutations in kinase are NOT cross-resistant to cidofovir or foscarnet
- Mutations in DNA pol may confer resistance to cidofovir or foscarnet (less frequent)

penciclovir
CMV
retinitis
prophylaxis
severe
myelosuppression
CMV
DNA Pol

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Valganciclovir

Monovalyl ester of ganciclovir
___ bioavailability (60%)
Rapidly hydrolyzed to ___ by esterases in intestine and liver
Used to treat CMV ___ in ___ patients

increases
ganciclovir
retinitis, AIDS

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Foscarnet

Inorganic pyrophosphate compound
(phosphonoformic acid)
Inhibits viral ___ , RNA polymerase, and HIV RT
does NOT require ___
Blocks ___ binding site of the viral DNA polymerase
Inhibits cleavage of pyrophosphate from dNTPs

MOA
- Carboxyl overlaps with binding site B-phosphate
- Phosphonates occupies position of g-phosphate
- Traps polymerase in ___ formation
- DNA is unable to ___

DNA polymerase
phosphorylation
pyrophosphate
closed
translocate

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Foscarnet

Pharmacokinetics
- Poor oral bioavailability
- Only administered ___
- Up to 30 % may be deposited in ___
- Renal clearance in proportion to CrCl

Clinical use
- ___ ___ (equivalent to ganciclovir)
- Dose must be titrated according to ___
- ___ with ganciclovir against CMV

Toxicity
- ___ insufficiency
- Hypo- or hyper ___
- Hypo- or hyper ___
- Headaches in 25% of patients

Resistance
- Mutations in DNA ___ or ___ RT
- Resistant CMV isolates are cross-resistant to ___
- Foscarnet usually still effective against cidofovir- resistant CMV

IV
bone
CMV retinitis
CrCl
synergistic
renal
phosphatemia, calcemia
DNA pol, HIV RT
ganciclovir

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Cidofovir

Acyclic nucleoside phosphonate analog of ___
- Phosphonate cannot be cleaved by cellular esterases - catabolically ___
- Phosphorylated by cellular kinases
- Intracellular half-life is 17 to 65 h

poor substrate for ___ DNA pol (1000x less efficient than dATP)

Broad spectrum of activity
- CMV, HSV-1, HSV-2, VZV, adenovirus, poxvirus, polyomavirus, and human papillomavirus

MOA:
- Highly selective for viral ___ ___
- Does NOT require activation by viral kinases
- ___ inhibitor and chain ___
- Chain termination by CMV pol requires two consecutive incorporations

Adverse effects
- Dose-dependent ___

Clinical use - CMV ___ (IV)

cytosine
stable
human
DNA pol
competitive, terminator
nephrotoxicity
retinitis

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Letermovir

Newest anti-herpes virus drug - approved 2017
- ___ of CMV infection and disease in adult allogenic hematopoietic stem cell ___ (HSCT) patients who have CMV

MOA: New class of inhibitor: ___
- highly specific for CMV
- Herpes virus DNA replication is through rolling circle mechanism - Individual genomes must be cut out by “terminase complex”
- inhibits ___ ___ by binding to pUL56 and preventing cleavage and packaging
- NO effect on protein synthesis or DNA replication

No cross resistance to other CMV drugs

prophylaxis, transplant
non-nucleoside
terminase complex

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Influenza virus

___ stranded RNA virus
- enveloped
- New virus strains can be created by
“___ ” - mixing of RNA segments

A: infects humans and many different animals, including ducks, chickens, pigs, whales, horses, and seals

B: widely circulates only in humans

C: causes a very mild disease

negative
reassortment

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Influenza A subtypes

Influenza A viruses are divided into subtypes based on two genes:
- ___ (H)
- ___ (N)
- Different subtypes can infect different
organisms

Hemagglutinin
Neuraminidase

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Influenza virus Neuraminidase

Essential for virus replication
- Located in virus ___

Facilitates virus dissemination
- ___ binds to terminal sialic acid residues
- Cleavage by ___ releases virus

membrane
HA
NA

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Neuraminidase inhibitors are ___ state analogs

mimic ___ acid

transition
sialic

Oseltamivir (Tamiflu)

___ - converted to active form by liver
esterases
- Metabolite is an effective inhibitor of ___

Active against influenza A and B
- Less effective against __ though

PK
- ___ (75% reaches systemic circulation)
- converted to oseltamivir carboxylate by hepatic esterases

generally well tolerated

need to initiate within ___ hrs of first symptoms
- gives you back a day

Resistance
- mutations in ___ active site
- influenza A with reduces susceptibilty
- develops more easily than in zanamavir

prodrug
NA
B
PO
48
NA

Zana binds a lot tighter so less affected by mutations of active site

Zanamivir

Transition state analog
Mechanism is same as ___
Effective against influenza A and B
Administered via oral ___

PK
- 4-17% of the inhaled dose is systemically
absorbed
- Excreted unchanged by the kidneys

Toxicity
- ___ : pls dont give this to people with COPD or asthma, that would be crazy

oseltamivir
inhaler
bronchospams

Peramivir – newest neuraminidase inhibitor

Transition state analog of ___ acid
- active against A and B
- ___ administration (ages 2+)

good for pts who:
- not responding to oral/inhaled
- need IV

sialic
IV

Baloxavir marboxil

Mechanism: inhibits viral “cap-snatching” (blocks ___ )
- Baloxavir marboxil binds to the PB2 subunit of the RNA polymerase of virus and inhibits the influenza cap-dependent endonuclease.
- Viral ___ can no longer be produced

Clinical indication: influenza within first ___ hours of symptoms (adults 12 yrs+)

Adverse effects: diarrhea, ___

transcription
mRNAs
48
bronchitis

Hepatitis C virus (HCV)

Small, ___ stranded RNA virus
- causes chronic liver infections
- Transmission is via contaminated blood - IV drug use

HCV makes a ___ polyprotein that is cleaved by viral and cellular proteases

MOAs:
- NS3/NS4A serine protease inhibitors (sim, boc, tela)
- NS5A inhibitors (dac)
- NS5B polymerase inh (sofo)

positive
single

# Anti-HCV treatments Previous standard of care: ___ plus pegylated interferon alpha Goal of treatment - Sustained virological response (SVR) - HCV RNA undetectable for 6 months after treatment

ribavirin

# Nonspecific defenses against viral infection Interferons induce synthesis of cellular proteins - strongly induced by viruses and dsRNA - have antiviral effects (specific to certain viruses) ___ - degrades viral RNA but not cellular RNA Protein kinase that phosphorylates and ___ EIF-2 (a translation initiation factor) Many viruses have evolved mechanisms to counteract the antiviral effects of interferons (boo)

- Ribonuclease - inactivates

# Interferon alpha as antiviral drug Recombinant protein produced by E. coli - IM or SC Pegylated interferon alpha - Increases half-life and reduces dosing frequency - supperior efficacy compared to non-peg COMBO WITH ___ more effective than mono of either one Clinical use: HCV, HBV, HHV-8, papillomavirus Toxicity - ___ like symptoms - May cause or aggravate ___ or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. woah - Patients should be monitored closely

- ribavirin - flu - fatal

# Ribavirin ___ analog with incomplete purine ring - ___ by cellular kinases to triphosphate form Broad spectrum of activity - influenza A, B - Hep A, B, C - genical herpes - herpes zoster - measles - hantavirus - lassa fever virus MOA: - Inhibition of ___ (IMPDH) - reduces ___ levels - Direct inhibition of viral RNA ___ - ___ into viral RNA leading to error catastrophe Clinical use - combo therapy for HCV - aerosol for treatment of RSV pneumonia in hospitalized children

- guanosine - phosphorylated - Inosine monophosphate dehydrogense, GTP - polymerase - Incorporation

# HCV Protease inhibitors Target the HCV protease ___ - Block cleavage of the HCV ___ - Linear peptide mimics - Ketoamide reversible ___ inhibitors - ___ trap – forms covalent link to active site Ser139

NS3 - polyprotein - covalent - serine

# HCV Protease inhibitors 2nd Gen P1-P3 substrate analogs - Macrocyclic peptides - Non- ___ inhibitors - All are substrates of ___ and weak inhibitors Example: ___ and ___

- non-covalent - CYP3A4 - simeprevir - paritaprevir

# HCV Protease inhibitors 2nd Gen P2-P4 substrate analogs Examples: ___ , ___ , and ___

- Grazoprevir - Voxilaprevir - Glecaprevir

T or F: 2nd gen HCV protease inhibitors have an induced fit

TRUE Induced pocket accommodates large heterocycle

# HCV Protease Inhibitors Advantages - once daily - well tolerated - Active against all genotypes except 3 Resistance - mutations in ___ active site - Low genetic barrier of resistance - Similar, but not identical pattern of mutations for linear and macrocyclic inhibitors - Retain activity against some NS3 mutants that developed resistance to 1st generation HCV PIs

NS3

# HCV RNA Polymerase inhibitors ___ = HCV RNA polymerase - Nucleoside RNA polymerase inhibitors - Example: ___ (Solvadi) ___ of 2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate - converted by liver enzymes - Triphosphorylated by cellular nucleotide kinases (YMPK and NDPK)

NS5B - Sofosbuvir - prodrug

# HCV RNA Polymerase inhibitors Sofosbuvir mechanism - Incorporated in viral RNA chain - Causes chain ___ (2’ Methyl group is critical) Genetic barrier for resistance - Single mutation in ___ site (S288T)

- termination - active

# HCV RNA Polymerase inhibitors Dasabuvir: Non ___ RNA polymerase inhibitors - 7,000-fold selectivity for HCV RNA Pol NS5B has 5 known binding sites MOA - Binds to palm I site of HCV RNA polymerase - Prevents ___ changes - Blocks ___ incorporation into viral RNA

- nucleoside - conformational - nucleotide

# HCV NS5A inhibitors ___ required for HCV RNA replication, but exact mechanistic role unknown Ledipasvir, Elbasvir, Daclatasvir, Velpatasvir, Pibrentasvir Inhibits both viral RNA ___ and assembly or ___ of infectious viral particles Resistance to HCV NS5A inhibitors 1st gen - lower genetic barrier - single mutations = high resisitance 2nd gen - higher genetic barrier - Retain activity against common resistance- associated substitutions

- NS5A - replication, release | 2nd gen are tougher

# HCV inhibitor summary HCV NS3 protease inhibitors (-previr) (3)

Grazoprevir Voxilaprevir Glecaprevir

# HCV inhibitor summary HCV NS5A inhibitors (-asvir) (5)

- Ledipasvir - Daclatasvir - Velpatasvir - Pibrentasvir - Elbasvir

# HCV inhibitor summary HCV NS5B inhibitors (-buvir) (2)

- Sofosbuvir - Dasabuvir

# Black Box warning for HCV direct acting antivirals (DAA) Hepatitis B virus (HBV) ___ has occurred in patients co- infected with hepatitis C virus (HCV) while undergoing treatment with DAAs for HCV infection - **observed with DAAs used without ___** - often followed by hepatitis, and, in severe cases, hepatic failure, and death. To decrease risk - screen for HBV infection before initiating - monitor for flare/reactivation - Consult a physician with expertise in managing hepatitis B - counsel pts to contact healthcare professional when they notice s/sx

reactivation interferon

# Hepatitis B virus - Can cause chronic liver infections that lead to cirrhosis and hepatocellular carcinoma - ___ available Life cycle - Partially dsDNA virus - Viral genome replication includes an RNA intermediate that is converted to viral DNA by ___ Anti HBV drugs

- vaccine - RT

# Anti HBV drugs Anti-Retrovirals: Tenofovir and Lamivudine Others: telbivudine, entecavir, adefovir Mechanism - Telbivudine - L-isomer of ___ - causes DNA chain ___

- thymidine - termination

# Anti HBV drugs - Nucleotide inhibitors Tenofovir disoproxilfumarate ___ - converted to tenofovir Acyclic nucleoside phosphonate analog of ___ Phosphonate cannot be cleaved by cellular esterases - catabolically ___

- prodrug - adenosine - stable

# SARS-CoV-2 Remdesivir Broad spectrum antiviral ___ that is bio-transformed to a ribonucleotide analog that can inhibit viral RNA ___ - administered IV - Originally developed to treat hepatitis C and has been investigate for use against Ebola virus, Marburg virus, measles and others

prodrug polymerase

# Nirmatrelvir - ___ bioavailable inhibitor of SARS-CoV-2 3C-like ___ (3CLpro). 3CLpro cleaves polyprotein 1a and 1ab of SARS- CoV-2 - Patients with mild to moderate COVID-19 ages 12 and older and within __ days of symptom onset - Peptidomimetic inhibits active site ___ residue in 3CLpro. Can no longer make active nonstructural proteins from the __ 300 mg nirmatrelvir with 100 mg ritonavir (2x day). Ritonavir used to boost nirmatrelvir levels by inhibiting ___

- orally, protease - 5 - cysteine - polyprotein - CYP3A4

# Molnupiravir ___ of a synthetic nucleoside derivative N4-hydroxycytidine and serves as a ___ inhibitor and chain ___ Originally developed to treat influenza. Indicated for mild to moderate COVID-19 for adults with high risk of severe COVID-19 progression ___ potential found in bacterial cells (Ames test) as well as in fetal rats and can increase virus mutagenic potential

- prodrug, polymerase, terminator - mutagenic