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8/15/2019 Protease Inhibitor
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Protease inhibitor (pharmacology)
From Wikipedia, the free encyclopedia
Jump to: navigation, search For natural protease inhibitors, see protease inhibitor (biology).
Protease inhibitors (Ps) are a class of drugs used to treat or prevent infection by viruses,
including !" and !epatitis #. Ps prevent viral replication by inhibiting the activity of
proteases, e.g. !"$% protease, en&ymes used by the viruses to cleave nascent proteins for
final assembly of ne' virions.
Protease inhibitors have been developed or are presently undergoing testing for treating
various viruses:
• !"*+: antiretroviral protease inhibitors (sauinavir , ritonavir , indinavir ,
nelfinavir , amprenavir-% etc.)
• !epatitis #: /oceprevir
• !epatitis #: 0elaprevir
1iven the specificity of the target of these drugs there is the risk, as in antibiotics, of the
development of drug$resistant mutated viruses. 0o reduce this risk it is common to use several
different drugs together that are each aimed at different targets.
Contents
• % ntiretrovirals
• 2 ntiproto&oal ctivity
• 3 nticancer ctivity
• 4 +ide 5ffects
• 6 +ee also
• 7 8eferences
• 9 5ternal links
Antiretrovirals
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Protease inhibitors 'ere the second class of antiretroviral drugs developed. n all cases,
patents remain in force until 2;%; or beyond.
NameTrade
nameCompany Patent Notes
+auinavir Fortovase,
nvirase
!offmann<=a
8oche
>.+.Patent
6,%?7,43@
t 'as the first protease inhibitorapproved by the F* (*ecember 7,
%??6).
8itonavir Aorvir bbott
=aboratories
>.+.
Patent
6,64%,2;7
$
ndinavir #riivan Berck C #o.
>.+.
Patent
6,4%3,???
$
Aelfinavir "iracept
gouron
Pharmaceuticals
>.+.
Patent6,4@4,?27
$
mprenavir generase 1lao+mithDline
>.+.
Patent
6,6@6,3?9
0he F* approved it pril %6,
%???, making it the siteenth F*$
approved antiretroviral. t 'as the
first protease inhibitor approved for
t'ice$a$day dosing instead of
needing to be taken every eight
hours. 0he convenient dosing came
at a price, as the dose reuired is
%,2;; mg, delivered in eight very
large gel capsules. Production 'asdiscontinued by the manufacturer
*ecember 3%, 2;;4, as it has been
superseded by fosamprenavir.
=opinavir Daletra bbott $s only marketed as a combination,
'ith ritonavir .
ta&anavir 8eyata&/ristol$Byers
+uibb$
0he F* approved it on June 2;,
2;;3. ta&anavir 'as the first P
approved for once$daily dosing. t
appears to be less likely to cause
lipodystrophy and elevated
cholesterol as side effects. t may
also not be cross$resistant 'ith
other Ps.
Fosamprenavir =eiva,
0el&ir
1lao+mithDline $ s a prodrug of amprenavir. 0he
F* approved it Ectober 2;, 2;;3.
0he human body metaboli&es
fosamprenavir in order to form
amprenavir, 'hich is the active
ingredient. 0hat metaboli&ation
increases the duration that
amprenavir is available, makingfosamprenavir a slo'$release
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Protease inhibitors can cause a syndrome of lipodystrophy, hyperlipidaemia, diabetes mellitus
type 2, and kidney stones.-%2
See also
• *avid !o $ *+ researcher 'ho pioneered the use of protease inhibitors in treating
!"$infected patients
• 0he Proteolysis Bap
• 8everse transcriptase inhibitor
References
%. 8ang, !. P., *ale, B. B., 8itter, J. B., C Flo'er, 8. J. (2;;9). 8ang and*aleHs Pharmacology (7th 5dition ed.). Philadelphia: #hurchill =ivingstone 5lsevier.
2. 1uidelines for the >se of ntiretroviral gents in !"$%$nfected dults
and dolescents, Aovember 3, 2;;@, *eveloped by the *!!+ Panel on ntiretroviral
1uidelines for dults and dolescents < Working 1roup of the Effice of *+
8esearch dvisory #ouncil (E8#). full guidelines.
3. Badruga J", /erger *, BcBurchie B et al (Jul 2;;9). 5fficacy and safety
of darunavir$ritonavir compared 'ith that of lopinavir$ritonavir at 4@ 'eeks in
treatment$eperienced, !"$infected patients in 00A: a randomised controlled
phase trial. Lancet !"# (?6@%): 4?<6@. doi:%;.%;%7+;%4;$7937(;9)7%;4?$7. PB* %97%9292.
4. =i& !ighleyman, Patient dvocates #ommend Pricing of Ae' P *arunavir,
http:'''.hivandhepatitis.comrecent2;;7ad%;73;;7Ka.html
6. -*arunavir $ first molecule to treat drug$resistant !", http:'''.ne's$
medical.netLidM%?2%%
7. /orman + (2;;7). 8etaining 5fficacy gainst 5vasive !": *arunavir
analog to *+$virus shapeshifters: 8esistance may be futile. Chemical &
Engineering News $% (34): ?.
9. *unn =, ndre's D0, Bc#arthy J+ et al (2;;9). 0he activity of protease
inhibitors against 1iardia duodenalis and metronida&ole$resistant 0richomonas
vaginalis. Int. J. ntimicro!. gents &' (%): ?@<%;2.
doi:%;.%;%7N.iNantimicag.2;;7.;@.;27. PB* %9%39962.
@. ndre's D0, Fairlie *P, Badala PD et al (2;;7). Potencies of !uman
mmunodeficiency "irus Protease nhibitors n "itro against Plasmodium falciparum
and n "ivo against Burine Balaria. ntimicro!. gents Chemother. # (2): 73?<4@.
doi:%;.%%2@#.6;[email protected];;7 . PB# %377?;;. PB* %743792%.
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?. *oyle P+, Ghou OB, 5ngel J#, BcDerro' J! (2;;9). #ysteine Protease
nhibitor #ures #hagasH *isease in an mmunodeficient$Bouse Bodel of nfection.
ntimicro!ial gents and Chemotherapy (%%): 3?32<?. doi:%;.%%2@#.;;437$
;9. PB# 2%6%42?. PB* %97?@726.
%;. J.J. 1ills et al (2;;9). Aelfinavir, =ead !" Protease nhibitor, s a/road$+pectrum, nticancer gent that nduces 5ndoplasmic 8eticulum +tress,
utophagy, and poptosis n vitro and n vivo. Clinical Cancer "esearch ! (%9):
6%@3<?4. doi:%;.%%6@%;9@$;432.##8$;9$;%7%. PB* %99@6696.
%%. a b Pyrko, P.I Dardosh, I Wang, WI Qiong, WI +chRnthal, !I #hen, 0#
(2;;9). !"$% protease inhibitors nelfinavir and ata&anavir induce malignant glioma
death by triggering endoplasmic reticulum stress. Cancer "esearch *" (22): %;?2;<
@. doi:%;.%%6@;;;@$6492.#A$;9$;9?7. PB* %@;;7@39.
%2. Protease nhibitor$ssociated *iabetes Bellitus: Potential #ause of
Borbidity and Bortality =ori 5. Fantry uthors and *isclosures Posted: ;3242;;3IJ cuir mmune *efic +yndr. 2;;3I32(3) S 2;;3 =ippincott Williams C Wilkins
E+ternal lin,s
• brief history of the development of protease inhibitors by !offman =a 8oche,
bbott, and Berck
-hide.
v
t
e
Antiviral dr/gs0 antiretroviral dr/gs /sed against 123 (primarily 4#)
Entry5f/sion
inhibitors
( Discovery &
development )
• gp#$ (5nfuvirtide)
• CC"% (Baraviroc
• "icrivirocT, #enicrivirocT, P8E %4;T)
• C# (bali&umabT)
Reverse6
transcriptaseinhibitors (RT2s)
N/cleoside 7
N/cleotide (NRT2) • Nucleoside analogues ' N"(Is)
bacavir (/#)UV
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• 5mtricitabine (F0#)UV
• =amivudine (30#)UV
• *idanosine (dd)V
• Gidovudine (G0)V
• pricitabineT
• +tampidineT
• 5lvucitabineT
• 8acivir T
• mdoovir T
• +tavudine (d40)V
• Galcitabine (dd#)
• Festinavir T
• Nucleotide analogues ' Nt"(Is)
0enofovir UV
• 1+ 934;
Non6N/cleoside
(NNRT2)
( Discovery &
development )
• *$ st generation+ Efaviren, -
• AevirapineV
• =oviride
• *elavirdine
•
*/nd generation+ diarylpyrimidines
(5travirine
• 8ilpivirine)
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• =ersivirineT
2ntegrase inhibitors
• 8altegravir
• 5lvitegravir T
• *olutegravir T
• 1loboidnan (eperimental)
• BD$2;4@T
• / 224437T
8at/ration
inhibitors
• /evirimatT
• "iveconT
Protease 2nhibitors
(P2)
( Discovery and development )
st generation
• Fosamprenavir U
• =opinavir UV
• Aelfinavir V
• 8itonavir V
• +auinavir V
• mprenavir
• ndinavir V
&nd generation
• ta&anavir U
• *arunavir
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• 0ipranavir
Combined
form/lations
• =amivudine&idovudine
• 5mtricitabinetenofovirefaviren&
• bacavirlamivudine&idovudine
• 0enofoviremtricitabine
• =opinavirritonavir
• bacavirlamivudine
• 5mtricitabinerilpivirinetenofovir
E+perimental agents
9ncoating inhibitors • 08B6alpha (gene)
Transcriptioninhibitors
• 0at antagonists
Translation inhibitors • 0richosanthin
:ther
• b&yme
• #alanolide
• #eragenin
• #yanovirin$A
• *iarylpyrimidines
• 5pigallocatechin gallate (51#1)
• Foscarnet
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• 1riffithsin
• !ydroycarbamide
• Biltefosine
• Portmanteau inhibitors
• +eliciclibT
• +ynergistic enhancers
• 0re recombinase
• Ginc finger protein transcription
factor
• DP$%47%T
• #obicistatT
;ailed agents
• *eelvucitabine
• #apravirine
• 5mivirine
• =odenosine
• tevirdine
• /recanavir
• plaviroc
•VW!E$5B
•XWithdra'n from market
• #linical trials:
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oTPhase
oY Aever to phase
U*!!+ preferred first$line agent. Formerly or rarely used agent.
B: "8
-hide.
v
t
e
<NA vir/s antivirals (primarily 4#= also S#A< and <#*>>)
>altimore 21erpesvir
/s
<NA6
synthes
is
inhibito
r
T?
activate
d
P/rine
analog/e
• guanine
(ciclovir V"alacyclovir
• 1anciclovir "alganciclovir
• Penciclovir Famciclovir )
• adenine ("idarabine)
Pyrimidi
neanalog/e
• uridine (douridine
• 0rifluridine
• 5doudine)
• thymine (/rivudine)
• cytosine (#ytarabine)
Not T?
activate
d
• Foscarnet
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:ther
• *ocosanol
• early protein (Fomivirsen)
• 0romantadine
1P358C
• miuimod8esiuimod
• Podophyllotoin
3accinia • assem!ly) 8ifampicin
Po+viridae • Bethisa&one
1epatitis >
(322)
• Nucleoside analogues ' N"(Is) 5ntecavir
• =amivudine
• 0elbivudine
• #levudine
• Nucleotide analogues ' Nt"(Is) defovir
• 0enofovir
8/ltiple5gener
al
N/cleic acid inhibitors • #idofovir
2nterferon
• nterferon alfa$2b
• Peginterferon alfa$2a
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8/ltiple5/n,no@n
• 8ibavirinV0aribavirin
• Boroydine
•VW!E$5B
•XWithdra'n from market
• #linical trials:
oTPhase
oY Aever to phase
B: "8
-hide.
v
t
e
Pharmacology0 enzyme inhibition
Class#ompetitive inhibition B >ncompetitive inhibition B Aon$competitive inhibition B
+uicide inhibition B Bied inhibition
S/bstrat
e
:+idored/ctase
(EC )
%.% ldose reductase B !B1$#o reductase
%.3 6$alpha$reductase
%.4 Bonoamine oidase
%.6 *ihydrofolate reductase
%.%3 =ipoygenase
%.%4 romatase B #EQ$2
%.%9 Qanthine oidase B 8ibonucleotide reductase
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Transferase (EC
&)
2.% #EB0 B 0hymidylate synthase
2.4 P8P
2.6 *ihydropteroate synthetase B Farnesyltransferase
2.7 1/ transaminase
2.9 Aucleotidyltransferase (ntegrase, 8everse transcriptase) B
Protein kinase (0yrosine$kinase (Janus kinase))
1ydrolase (EC !)
3.% Phosphodiesterase B cetylcholinesterase B 8ibonuclease
3.2 Polygalacturonase B Aeuraminidase B lpha$glucosidase
3.4 Protease: E0opeptidase (*ipeptidyl peptidase$4, #5) B
Endopeptidase (0rypsin, 8enin, Batri metalloproteinase)
3.6 !istone deacetylase B /eta$lactamase
yase (EC %)4.% *opa decarboylase
4.2 #arbonic anhydrase