Medicinal Chemistry of Antiviral Agents Flashcards
1
Q
DNA chain terminators
A
-acyclovir
-molnupiravir
-cidofovir
-penciclovir (short chain terminator)
2
Q
Which antivirals can be incorporated into DNA
A
-acyclovir
-sofobuvir
-telbivudine
3
Q
Antiviral Prodrugs
A
-famciclovir (penciclovir)
-oseltamivir
-sofosbuvir
-tenofovir
-remdesivir
-molnupiravir
-valacyclovir
-valganciclovir
4
Q
antiviral cross-resistance
A
-foscarnet with ganciclovir
-penciclovir cross resistant with acyclovir
5
Q
How does foscarnet act on DNA polymerase
A
carboxyl overlaps w/ binding site beta phosphate
-traps polymerase in closed formation
-DNA is unable to translocate
6
Q
Metabolism of cidofovir
A
phosphorylated by cellular kinases
7
Q
why do valacyclovir and valganciclovir have greater bioavailability
A
prodrugs
8
Q
Herpes viruses
A
-large double-stranded DNA viruses
- can cause latent infections
- enveloped
9
Q
HSV-1
A
- commonly oral, but can cause genital herpes
10
Q
HSV-1 reactivation
A
-lips
11
Q
HSV-1 establishes latency in
A
trigeminal ganglion
12
Q
HSV-2
A
-commonly causes genital herpes
-can cause oral
13
Q
HSV-2 is more common in which populations
A
-women
-african americans
14
Q
HSV-1 usually infect as
A
children
15
Q
HVS-2 commonly infects
A
teenagers or adults
16
Q
HSV-2 establishes latency in
A
the sacral ganglion
17
Q
HSV-2 reactivates in
A
genital area
18
Q
Varicella zoster virus (VZV)
A
-primary infection -> chickenpox
-causes shingles
19
Q
VZV latent in
A
ganglia area of infection
20
Q
VZV reactivation
A
-shingles
- in response to stress or decreased immune function
21
Q
Shingles
A
rash and blisters that scab over
22
Q
VZV complication
A
postherpetic neuralgia (PHN)
23
Q
VZV transmission
A
shingles isnt transmitted but virus can cause chicken pox
24
Q
VZV prevention
A
- 2 doses of shingrix
- separated by 2 to 6 months
- all immunocompetent adults 50 and older
25
Cytomegalovirus (CMV)
-80% of adults infected
-mild or no symptoms
26
CMV can be severe if
-infection occurs during fetal development
-> congenital abnormalities
->infant can also be infected during birth
- infection occurs in immunocompromised people
27
Anti- herpesvirus agents
- acyclovir
- valacyclovir
- penciclovir
- ganciclovir
- valganciclovir
- cidofovir
- foscarnet
28
Acyclovir is derived from
acyclic guanosine
29
Acyclovir Structure Function
-lacks 3' hydroxyl
- selectively accumulates in infected cells
-> higher concentration in infected cells
-> high ratio of therapeutic value to toxicity
30
Acyclovir requires ____ phosphorylation events
3
31
Acyclovir MOA
-competitive inhibitor of viral dna polymerase
->competes w/ dGTP
-> dna polymerase becomes bound to template irreversibly
-Chain terminator
-incorporated into DNA
32
chain terminators MOA
-prevent dna synthesis
33
Acyclovir spectrum of activity
-active against HSV-1, HSV-2, and VZV
-reduced activity against cytomegalovirus
34
Acyclovir PK
-bioavailability low (15-30%)
-bioavailability not affected by food
35
Acyclovir AEs
-well tolerated
- infrequent nausea, diarrhea, rash, or HA
- very rarely renal insufficiency or neurotoxity
36
Acyclovir Resistance
-mutations in viral thymidine kinase *
- mutations in viral dna polymerase
37
Valacyclovir
-l-valyl ester of acyclovir
-rapidly converted to acyclovir by esterases in liver and intestine
38
Valcyclovir bioavailability
48-54%
improved efficacy compared to acyclivir
39
valacyclovir is transported by
intestinal amino acid transporters
40
Famciclovir
-prodrug of penciclovir
-converted in intestine and liver by first pass metabolism
41
Famciclovir & Penciclovir MOA
-activated by viral and cellular kinases
-competitive inhibitor of viral DNA polymerase
-does NOT cause immediate chain termination (allows short chain elongation)
42
Cross resistance confer to penciclovir and acyclovir by
viral kinase mutants
43
clinical uses of famciclovir and penciclovir
oral famciclovir
-> primarmy and recurrent genital herpes
-> acute herpes zoster
topical penciclovir
-recurrent herpes labialis
44
Famciclovir and penciclovir PK
70% bioavailable
45
Famciclovir and penciclovir AEs
well tolerated
46
Ganciclovir
-similar to penciclovir
-same moa as penciclovir
47
Ganciclovir is a better substrate for
CMV
-100x more potent against CMV
48
Ganciclovir PK
6-9% bioavailability
49
Ganciclovir uses
-iv, oral, and intraocular implants can be used to treat CMV retinitis
- oral can be used for CMV prophylaxis
50
Ganciclovir Toxicity
-more severe than acyclovir
-> myelosuppression
51
Ganciclovir Resistance
-due to mutations in CMV kinase (UL97 gene) or CMV DNA pol (UL54)
-kinase mutations are not cross-resistant
-DNA pol may confer resistance to cidofovir or foscarnet (less frequent)
52
Valganciclovir
-monovalyl ester of ganciclovir
53
valganciclovir PK
60% bioavailability
54
Valganciclovir MOA
rapidly hydrolyzed to ganciclovir by esterases in intestine and liver
55
Valganciclovir use
CMV retinitis in AIDs patients
56
Foscarnet
Inorganic pyrophosphate compound
57
Foscarnet MOA
-inhibits viral DNA polymerase, RNA polymerase, and HIV RT
- blocks pyrophosphate binding site of the viral DNA polymerase
-inhibits cleavage of pyrophosphate from dNTPs
58
Foscarnet ________ require phosphorylation for activity
DOES NOT
59
Foscarnet structure function
-carboxyl overlaps with binding site b-phosphate
-phosphonates occupies position of gamma phosphate
- traps polymerase in closed formation
-dna is unable to translocate
60
Foscarnet PK
-poor oral bioavailability
-iv
-30% deposited in bone
- renal clearance in proportion to creatinine
61
Foscarnet use
-CMV retinitis
-synergistyc with ganciclovir against CMV
62
Foscarnet toxicity
-renal insufficiency
-hypo or hyperphosphatemia
-hypo or hypercalcemia
-HA
63
Foscarnet Resistance
-mutations in DNA pol or HIV RT
-resistant CMV isolates are cross-resistant to ganciclovir
-usually still effective against cidofovir-resistant CMV
64
Cidofovir is an acyclic nucleoside phosphonate analog of
cytosine
65
Cidofovir PK
-catabolically stable
-phosphorylated by cellular kinases
- t1/2 17 to 65h
-poor substrate for cellular DNA polymerase
66
Cidofovir activity
-CMV, HSV-1, HSV-2, VZV, adenovirus, poxvirus, polyomavirus, and human papillomavirus
67
Cidofovir is highly selective for
Viral DNA pol
68
Cidofovir MOA
-competitive inhibitor and chain terminator (requires two consecutive incorporations)
69
Cidofovir AEs
dose - dependent nephrotoxicity
70
Cidofovir Use
-CMV retinitis (intravenous)
71
Letermovir use
prophylaxis of CMV infection and disease in adult allogeneic hematopoietc stem cells
72
letermovir class of inhibitor
non-nucleoside
73
letermovir is highly specific for
CMV
74
letermovir moa
-inhibits terminase complex
-> binds pUL56
-> prevents cleavage and packaging
75
letermovir Resistance
no cross resistance to other CMV drugs
76
influenza virus
-negative stranded RNA virus
-enveloped
-humans, birds, pigs, horses, ect
-new strands created by reassortment
77
Influenza A
infects humans and many different animals
78
Influenza B
widely circulates only in humans
79
Influenza C
very mild disease
80
influenza A & B cause
epidemics nearly every winter
81
influenza vaccine protects against
A & B strains circulating
82
Influenza A subtypes
-hemagglutinin (H)
-Neuraminidase (N)
83
There are ___ H genes and ___ N genes
16H; 9N
84
Each influenza A virus has
one H and one N
85
neuraminidase inhibitors moa
-halts viral replication
-prevents virion release
86
neuraminidase inhibitors
-sialic acide
-DANA
-zanamavir
-oseltamivir
87
Oseltamibir (Tamiflu)
- prodrug
- metabolite inhibits NA
- influenza A&B
-> less effective against B
88
oseltamivir PK
-readily absorbed from GI tract after oral administration
-extensively converted by hepatic esterases to oseltamivir carboxylate
89
Oseltamivir Toxicity
-well tolerated
- n/v
90
Oseltamivir Use
-influenza A&B
-use in first 48h of first symptoms
-one day reduction in time to improvement
91
Oseltamivir Resistance
-mutations in active site of neuraminidase
92
NA inhibitor resistance mutations
-Arg292Lys
-Asn294Ser
-His274Tyr
93
Zanamivir
-transition state analog
-same mechanism as oseltamivir
94
Zanamivir is effective against
influenza A & B
95
Zanamivir Administration
oral inhaler
96
Zanamavir PK
-4-17% systemically absorbed
-excreted unchanged in kidneys
97
Zanamavir Toxicity
-bronchospasm
-not recommended for pts w/ copd or asthma
98
Peramivir
-transition state analog of sialic acide
99
Peramivir is active against
influenza A & B
100
Peramivir administration
IV or injectable (ages 2 and up)
101
Peramivir is appropriate for which patients
-not responding to either po or inhaled antiviral
-drug delivery via another route is not dependable or feasible
- other circumstances
102
Baloxavir Marboxil moa
-inhibits viral "cap-snatching"
-blocks transcription
103
Baloxavir marboxil indication
influenza w/in first 48h (12 and up)
104
Baloxavir marboxil AEs
diarrhea, brochitis
105
Hep C virus
-small, positive stranded RNA
106
Hep C virus causes
-chronic liver infections
-chronic hepatitis
-liver cirrhosis
-hepatocellular carcinoma
107
Hep C is transmitted via
contaminated blood
108
Anti-HCV treatment goal
-sustained virological response (SVR)
-> undetectable for 6mo after treatment
109
interferons induce
synthesis of cellular proteins
110
Interferon alpha
-recombinat protein (E. coli)
-non-glycosylated
111
interferon alpha PK
-not absorbed orally
- absorption exceeds 80% following IM or SQ injection
112
Pegylated interferon alpha
-linear or branches polyethylene glycol attached
- increases t1/2 and reduces dosing frequency
-superior efficacy to non-pegylated interferon
113
Interferon alpha is more effective when combined with
ribavirin
114
clinical uses for interferon alpha
-HCV
-HBV
-human herpes virus 8
-papillomavirus
115
interferon alpha toxicity
-flu like symptoms
-may cause or aggravate fatal or life threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders
-monitor closely
116
Ribavirin
-guanosine analog w/ incomplete purin ring
117
ribavirin is phosphorylated by _____ to ______ form
cellular kinase ; triphosphate
118
Ribavirin spectrum of activity
-influenza A & B
-hep A, B, C
-genital herpes
-herpes zoster
-measles
-hantavirus
-lassa fever virus
119
Ribavirin MOA
-inhibition of inosine monophosphate dehydrogenase -> reduces GTP levels
-direct inhibitation of viral RNA polymerase
-incoporation into viral RNA -> error catastrophe
120
Ribavirin clinical use
-combo therapy for hep C
-aerosol for RSV
121
HCV protease inhibitors MOA
- block cleavage of HCV polyprotein
-target HCV protease NS3
122
2nd gen protease inhibitors MOA
-linear peptide mimics
-ketoamide reversible covalent inhibitors
-serine trap - forms covalent link to active site Ser139
123
2nd gen HCV protease inhibitor P1-P3 substrate analogs
-simeprevir
-paritaprevir
124
All HCV protease inhibitors are substrates of _______ and ______ inhibitors
CYP3A4; weak
125
second gen HCV protease inhibitors P2-P4 substrate analogs
-grazoprevir
-voxilaprevir
-glecaorevir
126
Advantages of HCV protease inhibitors
-qd dosing
-well tolerated
-active against all genotypes except 3
127
HCV protease inhibitors resistance
-mutations in NS3 active site
128
HCV RNA polymerase inhibitors
-NS5B = HCV RNA polymerase
- nucleoside RNA polymerase inhibitors
129
Nucleoside RNA polymerase inhibitors
-sofosbuvir (Solvadi)
130
Sofosbuvir
-prodrug of 2'-deoxy-2'-fluoro-2'-C-methyluridine
monophosphate
131
Sofosbuvir activation
-converted by monophosphate by liver enzymes
-triphophorylated by cellular nucleotide kinases
-> uridine-cytidine monophosphate kinase (YMPK)
-> nucleoside diphosphate kinase (NDPK)
132
Sofosbuvir MOA
-incorporated in viral RNA chain
-causes chain termination
-> 2' methyl group is critical
133
Sofosbuvir genetic barrier for resistance
-single mutation in active site (S288T)
134
Non-nucleoside HCV RNA polymerase inhibitor
-dasabuvir
135
Dasabuvir is not active against
HCV genotype 2, 3, and 4 polymerases
136
Dasabuvir MOA
-binds to palm I site of HCV RNA polymerase
-prevents conformational change
-blocks nucleotide incorporation into viral RNA
137
HCV NS5A Inhibitors
-bind NS5A tightly
-inhibits both RNA replication and assembly or release of infectious viral particles
138
Ledipasvir genotypes
1, 4, 5, and 6
139
Elbsvir genotypes
1 and 4
140
Daclastasvir genotypes
1 and 3
141
velpatasvir genotypes
1-6
142
second gen HCV NS5A inhibitors
-velpatasvir
-pibrentasvir
143
Pibrentasvir genotypes
1-6
144
HCV NS5A inhibitors Resistance: first gen
-low genetic barrier
-varies between genotypes
- single mutation confer high resistance
-similar resistance pattern
145
HCV NS5A inhibitors Resistance: second gen
-higher genetic barrier
-retain activity against common resistance associated substitutions
146
HCV NS3 protease inhibitors
(-previr)
-grazoprevir
-voxilaprevir
-glecaprevir
147
HCV NS5A inhibtors
(-asvir)
-Ledipasvir
-Daclatasvir
-Velpatasvir
-Pibrentasvir
- Elbasvir
148
HCV NS5B inhibitors
(-buvir)
-sofosbuvir
-dasbuvir
149
HCV direct acting antivirals (DAA) Black box warning
HBV reactivation can occur
-pts should be screened for HBV infection
-pts may develop fatigue, weakness, loss of appetite, n/v, yellow eyes or skin, or light-colored stools (signs of serious liver injury)
150
Hep B virus
-can cause chronic liver infections that lead to cirrhosis and hepatocellular carcinoma
-vaccine available
151
HBV Life Cycle
-partially double-stranded DNA virus
-viral genome replication includes a RNA intermediate that is converted to viral DNA by reveres transcriptase
152
Anti HBV Drugs
Anti-retrovirals:
-tenofovir
-lamivudine
Others:
-telbivudine
-entecavir
-adefovir
153
Telbivudine MOA
-L-isomer of thymidine
-incorporated into viral DNA
-Causes DNA chain termination
154
Nucleotide inhibitors
-Tenofovir disoproxilfumarate
155
Tenofovir disoproxilfumarate
- prodrug converted to tenofovir
-acyclic nucleoside phosphonate analog of adenosine
-phophonate cannot be cleaved by cellular esterases -> catabolically stable
156
Remdesivir
-broad spectrum antiviral
-prodrug
-bio-transformed to a ribonucleotide analog
-inhbits virial RNA polymerase
157
Remdesivir Administration
IV
158
Remdesivir use
-emergency use then approved for COVID-19
159
Nirmatrelvir
-inhibitor SARS-CoV-2 3C-like protease
160
nirmatrelvir use
-patients w/ mild to moderate COVID-19
-ages 12 and up
-w/in 5 days of symptom onset
161
Nirmatrelvir MOA
-peptidomimetic inhibits active site cysteine residue in 3CLpro
-can no longer make active nonstructural proteins from the polyprotein
162
Nirmatrelvir Dosing
300mg nirmatrelvir w/ 100mg ritonavir (2xx day)
163
Ritonavir MOA
-boosts nirmatrelvir levels by inhibiting CYP3A4
164
Molnupiravir
-prodrug of a synthetic nucleoside derivative N4-hydroxycytide
-polymerase inhibitor and chain terminator
165
Molnupiravir Toxicity
well tolerated (nausea/GI/dizziness)
166
Molnupiravir Indication
-mild to moderate COVID-19 for adult with high risk of severe COVID-19 progression
167
Maraviroc blocks
chemokine and CD4 receptors
168
Enfuvirtide blocks
attachment and fusion of HIV
169
Nucleoside RT inhibitors and non-nucleoside RT inhibitors act on
reverse transcription of HIV
170
Raltegravir acts on
Integrase enzyme
-prevents integration
171
protease inhibitors inhibit
maturation
172
Reverse transcriptase three activities
-RNA dependent DNA polymerase
-Ribonuclease H
- DNA-dependent DNA polymerase
173
Reverse Transcriptase
-copies plus-strand RNA to produce minus-strand
-degrades RNA template from RNA-DNA hybrid
-synthesizes plus-strand DNA from minus-strand DNA template
174
NRTIx interfere with
1st and 2nd strand DNA synthesis
175
RT DNA polymerase activity
incorporation of dCTP into growing DNA strand
-each nucleotide is phosphorylated 3x
-different enzymes are used for each phosphorylation and for each nucleoside
176
Nucleoside RT inhibitors MOA
-lack the 3' OH -> false nucleotides
- competitive inhibitor of reverse transcriptase
-DNA chain terminator -> inhibits elongation
177
backbone of HIV initial therapy
nucleotide RT inhibitors
178
preferred combination of NRTIs
-tenofovir and emtricitabine
-abacavir and lamivudine
179
NRTIs are activated by __________ to __________
cellular kinases ; triphosphate form
180
Deoxyadenosine analogs
-tenofovir
-Didanosine (ddI)
2’3’-dideoxyinosine
181
Deoxycytidine analogs
-lamividine(3TC)
-emtricitabine (FTC)
182
Deoxyguanosine analogs
-abacavir (ABC)
183
NRTIs must be ___________ and use ___________
phosphorylated; cellular
184
NRTIs MOA
-compete with normal nucleosides and NTRIs that are analogs of the same nucleoside
185
Tenofovir alafenamide (TAF) pros
-less kidney damage
- increased accumulation in lymphocytes
-fewer side effects
-better at targeting HIV
186
Tenofovir alafenamide (TAF) vs previous tenofovir prodrugs
activated by different pathway
187
TAF cons
-associated with higher lipid levels compared to tenofovir disoproxil fumarate
188
TAF is a component of
Genvoya
189
Genvoya componets
-elvitegravir
-cobicistat
-emtricitabine
-tenofovir alafenamide (TAF)
190
TAF is converted to
TFV -> TFV-DP
191
TAF activation
1) CatA
2) phosphonamidase -> TFV
#) nucleoside kinases -> TFV-DP
192
why is TAF dose lower that TDF dose
different activation pathway
-more TFV converted to TFV-DP than not
193
Activated NRTIs are incorporated into
growing DNA chain by RT
194
NRTIs have a _______ affinity for HIV RT than for cellular DNA polymerase
higher
195
TAF must be processed to ____ by cellular enzymes before __________
TFV; phosphorylation
196
Resistance to anti-HIV drugs is due to
-HIV polymerase being error prone
-RT inhibitors are unable to supress viral replication > 90%
-large amount of virus present
197
rate at which mutations appear for anti-HIV drugs is ________ related to serum drug concentration
inversely
198
NRTI resistance due to
-discriminatory mutations
-excision mutations
199
discriminatory mutations
-selectively impair ability of RT to incorporate analogues into DNA
200
excision mutations
-ATP molecule removes a nucleoside analogue after its incorporated
201
For resistance to NRTIs mutations are mainly located near
the RT active site
202
Individual NRTIs have a ______ genetic barrier of resistance
low
203
NRTIs AEs
mitochondrial toxicity
-> anemia, granulocytopenia, myopathy, peripheral neuropathy, pancreatitis
-> lactic acidosis and hepatic steatosis
-> lipoatrophy
204
Abacavir Black Box Warning
hypersensitivity reaction
-can be fatal
-malaise, dizziness, HA, GI disturbances
-associated w/ HLA-B*5701 allele
-must test before abacavir tx
205
Nonnucleoside RT inhibitors (NNRTIs)
-bind directly on RT
-do NOT compete w/ nucleotides for binding
-block RNA and DNA-dependent DNA polymerase activities
206
NNRTIs phosphorylation?
no
207
NNRTI MOA
-unproductive binding of nucleoside triphosphate to RT
-blocks polymerization
208
NNRTI single mutation in ________ can promote resistance
binding site
209
First gen NNRTIs
-nevirapine
-efavirenz
-delavirdine
210
Efavirenz
-cns side effects
-potentially teratogenic
-long half lief -> 40-55h
211
Efavirenz dose
600mg qd
212
Nevirapine (Viramune) dose
200mg bid
213
Delavirdine is rarely used due to ______________
poor PK
214
Second gen NNRTIs (drugs)
-etravirine
-rilivirine
215
second gen NNRTIs
-diaryl-pyrimidien -based molecule
-inherently flexible
-binds mutants that are resistant to other NNRTIs
216
NNRTI resistance is caused by mutations in
the binding site
217
NNRTI AEs
-rash
-drug-drug interaction
218
Nevirapine AEs
-hepatotoxiccity
-SJS
219
Efavirenz AEs
-neuropsychiatric
-teratogenic
220
NNRTI metabolism
-Metabolized by CYP3A
221
NNRTI CYP3A inducers
-efavirenz
-nevirapine
-etravirine
222
NNRTI CYP3A Inhibitors
-efavirenz
-delavirdine
223
Etravirine inhibits
CYO2C9 and CYP2C19
224
NNRTI drug interactions
-CYP3A4 inducers reduce levels
-> rifampin
-CYP3A4 inhibitors can increase levels
225
T/F:
NNRTIs are prodrugs
false
226
mutations that confer resistances to NNRTIs __________ resistance to NRTIs
do not cause
227
Integrase
not found in humans
228
Integrase Inhibitors (INI)
inhibit insertion of HIV DNA into human genome
229
INI AEs
-diarrhea
-nausea
-fatigue
-headache
-itching
230
INIs do not interact with _________
CYP450s
231
INI administration
PO
232
Integrase function
-insert HIV DNA into host cell DNA
-2 steps
-> 3' processing
-> strand transfer
233
INIs MOA
-block the strand transfer step
234
INIs (drugs)
-elvitegravir
-dolutegravir
-bictegravir
235
INI resistance is caused by
-primary mutations -> around site of binding
-secondary mutations
236
Elvitegravir is metabolized by
CYP3A4
237
Elvitegravir is only available in
a coformulation w/ cobicistat
-COBI
238
Cobicistat role
-not active against HIV
-boosts elvitegravir concentrations by inhibiting CYP3A4 metabolism
239
Dolutegravir
-less likely for mutations
-higher barrier for resistance
-long plasma t1/2
240
Bictegravir
-no HLA-B *5701 testing
-cannot use w/ rifampin
-rasies SCr -> kidney monitoring
-low risk of resistance
-few drug interactions
241
Cobicistat MOA
inhibits CYP3A4
242
HIV protease inhibitors
-peptidomimetic
-> bind active site , but does not allow cleavage
-transition state mimetics
243
HIV protease
-aspartic acid in active site
244
HIV protease
-aggregated at inner membrane of HIV cell surface
-Cuts itself free
-cuts other enzymes
245
p17 of HIV
remains attached to the membrane
246
p24, p9, and p7 form
the bullet shaped inner core of the virion
247
HIV protease MOA
-cleaves bond via hydrolysis
-> catalyzes addition of water to amide
-breaks down to two products, carboxylic acid and an amine
-binding causes a confirmation change -> "flaps" close , cannot accommodate gag-pol
248
HIV protease inhibitors (PIs)
-amide bond is replaced by non-cleavable linkages
249
PIs (drugs)
-saquinavir
-ritonavir
-indinavir
-nelfinvir
-amprenavir
-atazanavir
-fosamprenavir
-darunavir
-lopinavir
-darunavir
250
HIV PIs metabolism
CYP3A4
-high potential for drug interactions
251
HIV PI interactions
-delavirdine increases indinavir and saquinavir levels
-efavirenz reduces indavir and saquinavir levels
252
PI Boosting
-low doses of ritonavir inhibits CYP3A4
-reduces resistance
-CON: hyperlipidemia, drug-drug interactions
253
Atazanavir (ATV)
-qd dosing
-minimal lipid and glycemic effects
-efavirenz and tenofovir reduce ATV concentrations
254
Darunavir (DRV)
-preferred PI for initial antiretoviral combos
-makes extensive hydrogen bonds with protease backbone
-inhibits HIV protease dimmerization
-can inhibit both wild type and mutants that are resistant to other PIs
-most potent
255
Tipranovir (TVP)
-cyp3a4 substrate and inducer
-retains activity against proteases in highly treated pts
256
PI resistance
most mutations occurr
in or near substrate cleft of protease
257
Some protease mutations confer _________ to some PIs, but increase ________ to others
resistance; susceptibility
258
PI AEs
-hyperlipidemia
-insulin resistance and diabetes
-lipodytrophy
-Elevated liver enzymes
-increased bleeding risk in hemophiliacs
-drug-drug interactions
259
preferred HIV tx rgimens
-biktarvy
-triumeq
-dovato
-genvoya
260
biktarvy
-bictegravir (INI)
-emtricitabine (NTRI)
-tenofovir alafenamide (NTRI)
261
Triumeq
-dolutegravir (INI)
-abacavir (NRTI)
-lamivudine (NTRI)
262
dovato
-dolutegravir (INI)
-lamivudine (NTRI)
263
genvoya
-elvitegravir/cobicistat (INI)
-emtricitabine (NTRI)
-tenofovir alafenamide (NRTI)
264
long acting injecable HIV therapies
-cabotegravir (INI)
-rilpivirine (NNRTI)
-lenacapavir
265
Lenacapavir
-capsid inhibitor
-biannual injection
-binds HIV p24 protein
-prevents w/virus replication by preventing virus assembly of the capsids into stable structure
266
What class does acyclovir belong to?
Guanosine analog; viral DNA polymerase inhibitor; chain terminator.
267
What class does valacyclovir belong to?
Prodrug of acyclovir; same class (guanosine analog).
268
What class does famciclovir belong to?
Prodrug of penciclovir; guanosine analog, viral DNA polymerase inhibitor.
269
What class does penciclovir belong to?
Guanosine analog; short-chain terminator; DNA polymerase inhibitor.
270
What class does ganciclovir belong to?
Guanosine analog; active against CMV; DNA polymerase inhibitor.
271
What class does valganciclovir belong to?
Prodrug of ganciclovir; same class.
272
What class does foscarnet belong to?
Inorganic pyrophosphate analog; directly inhibits viral DNA polymerase.
273
What class does cidofovir belong to?
Acyclic nucleoside phosphonate analog; DNA polymerase inhibitor and chain terminator.
274
What class does letermovir belong to?
Terminase complex inhibitor; CMV-specific.
275
What class does oseltamivir belong to?
Neuraminidase inhibitor.
276
What class does zanamivir belong to?
Neuraminidase inhibitor.
277
What class does peramivir belong to?
Neuraminidase inhibitor.
278
What class does baloxavir marboxil belong to?
Cap-dependent endonuclease inhibitor; inhibits viral mRNA synthesis.
279
What class does sofosbuvir belong to?
Nucleoside analog; NS5B polymerase inhibitor.
280
What class does dasabuvir belong to?
Non-nucleoside NS5B polymerase inhibitor.
281
What class does ledipasvir belong to?
NS5A inhibitor.
282
What class does daclatasvir belong to?
NS5A inhibitor.
283
What class does elbasvir belong to?
NS5A inhibitor.
284
What class does velpatasvir belong to?
NS5A inhibitor.
285
What class does pibrentasvir belong to?
NS5A inhibitor.
286
What class does grazoprevir belong to?
NS3/4A protease inhibitor.
287
What class does voxilaprevir belong to?
NS3/4A protease inhibitor.
288
What class does glecaprevir belong to?
NS3/4A protease inhibitor.
289
What class does ribavirin belong to?
Guanosine analog; RNA synthesis inhibitor with broad antiviral activity.
290
What class does tenofovir belong to?
Acyclic nucleoside phosphonate; reverse transcriptase inhibitor (NRTI-like).
291
What class does entecavir belong to?
Guanosine analog; reverse transcriptase inhibitor.
292
What class does lamivudine belong to?
Cytidine analog; reverse transcriptase inhibitor.
293
What class does remdesivir belong to?
Adenosine analog; viral RNA-dependent RNA polymerase inhibitor.
294
What class does nirmatrelvir belong to?
3CL protease inhibitor (SARS-CoV-2).
295
What class does molnupiravir belong to?
Nucleoside analog; RNA mutagen and polymerase inhibitor.
