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Protease inhibitor (pharmacology)

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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superseded by fosamprenavir.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;.2.73?$74@.2;;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 

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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 

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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 

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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