Antivirals 1 Flashcards
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
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
CMV (cytomegalovirus)
Severe disease can occur if
- Infection occurs during ___ development
- Infection occurs in ___ people
- fetal
- immunocompromised
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
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
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
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
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
Clinical uses of famciclovir and penciclovir
Oral famciclovir
- Primary and recurrent ___ herpes
- Acute herpes ___
Topical penciclovir
- Recurrent herpes ___
70 % bioavailable
- genital
- zoster
- labialis
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
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
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
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
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
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
Influenza A subtypes
Influenza A viruses are divided into subtypes based on two genes:
- ___ (H)
- ___ (N)
- Different subtypes can infect different
organisms
- Hemagglutinin
- Neuraminidase
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
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
