Antiviral drugs

1. Antiviral Drugs- introduction, Viral replication
2. Anti-Viral drugs, Classification of Antiviral Drugs
3. Anti-Herpes virus, Acyclovir (Zovirax), MAO, Metabolism, synthesis
4. Other antiviral drugs
5. Anti HIV drugs
6. The Life Cycle of HIV
7. Classification of Anti-HIV drugs
8. Reverse Transcriptase Inhibitors: NRTIs
9. MAO, Synthesis of Zidovudine
10. Reverse Transcriptase Inhibitors: NNRTIs
11. Protease Inhibitors (PIs)

1. Antiviral Drugs
1

2. Introduction to the Viruses
General properties of viruses:
1-They are very small in size, from 20-300 m.
2-They contain one kind of nucleic acid (RNAorDNA) as their
genome.
3-They are metabolically inert because they do not possess
enzyme systems necessary for the synthesis of new viral
proteins.
4-so they are called as obligate intracellular parasites as they
replicate inside living cells.
5-They are only seen by electron microscope.
2

3. Classification of Viruses
Classical virus classification schemes have been based on the
consideration of major properties of viruses:
1-The type of nucleic acid which is found in the virion (RNA
or DNA, single stranded or double stranded)
2-The symmetry and shape of the capsid (Cubic, helical,
complex).
3-The presence or absence of an envelope (enveloped, naked)
4-The size of the virus particle.
5-Antigenicproperties.
6-Biologic properties, including naturalhostrange, mode of
transmission, vector relationship, pathogenicityetc.
3

4. Classification of Viruses:
DNA
Icosahedral Complex
Pox viruses
Naked
Enveloped
Papilloma virus
Herpes
viruses
Hepatitis B
4

5. Classification of Viruses:
a
5

6. Viruses are different from other Microbes
A virus cannotreplicate on its own
It must attachand entera host cell
Then the virus, uses the host cell’s energy to
synthesize their DNA, RNA and protein.
Viruses are difficult to kill because they live
inside the cells
Any drug that kills a virus may also kill cells
(host)
6

7. a
Viral Replication
7

8. Viral replication:
Stepsofviralreplication:
1.Recognization
2-Attachment/Adsorption:
Virusattachestothecellsurfaceofthehost.
3-Penetrationbyfusion(Entry):
Somevirusinjecttheirnucleicacidthroughthecell
membrane.
Theviralenvelopeofsomevirionsfuseswiththeplasma
membraneandthenucleocapsidisthenintroducedinto
thecell.
Othersenterthecellintactandarethenuncoated(the
virionsaretakenintothecellbyendocytosiswherethe
cellmembranewrapsitselfroundthevirionandisthen
pinchedofftoproduceavesiclecalledanendosome)
8

9. 4-Uncoating:
Uncoatingisthephysicalseparationofviralnucleicacidfromthe
outerstructuralcomponents.Thisisdonebylysosomesofhost.
5-Transcription6.proteinsynthesis&7.Replication.
EarlygenestakesoverthehostcellsuchthatviralDNAand/orRNA
issynthesizeddependingonthetypeofvirus.
5-Synthesisofviralcomponents:
Thisinvolvesthesynthesisofviralproteinsandviralgenomes.
8-Assembly:
lategenesdirectthesynthesisofcapsid&Viralnucleicacidisthen
takenintothecapsidtoformthenucleocapsid.
9-Release:
Virusmaybereleasedfromthehostcelltoattackotherhost
cell.
9

10. Anti-Viral drugs
Key characteristics of antiviral drugs
Drugs used in treatment of viral infection are
called antiviral drugs
Many antiviral drugs arePurine or Pyrimidine
analogs.
Many antiviral drugs are Prodrugs.
So, these drugs phosphorylatedby viralcellular
enzymesin order to become active.
Anti-viral agents inhibits active replication.
10

11. Anti-viral howthey act?
Somedrugsinterferewithabilityofvirustobindto
cells.
Drugsareabletoenterthecellsinfectedwithvirusand
Interferewithviralnucleicacidsynthesisand/or
regulation.
Somedrugsstimulatethebody’simmunesystem.
Ahealthyimmunesystemworkssynergisticallywiththe
drugstoeliminateorsuppressviralactivity
11

12. Classification of Antiviral Drugs
CLASSES DRUGS
1. Anti-Herpes virus Idoxuridine,Trifluridine
Acyclovir,Valacyclovir,
Famciclovir
Ganciclovir,Valganciclovir
Cidofovir
Foscarnet
Fomivirsen
2. Anti-influenza virus Amantadine,Rimantadine
Oseltamivir,Zanamivir
3. Anti-Hepatitis Lamivudine, Adefovirdipivoxil,
Tenofovir
Primarily for Hepatitis C Ribavirin, Interferon α
12

13. CLASSES DRUGS
4. Anti-retrovirus
a. Nucleoside reverse
transcriptaseinhibitors (NRTIs)
Zidovudine(AZT), Didanosine,
Stavudine
Lamivudine, Abacavir,
Emtricitabine
Tenofovir(NtRTI)
b. Non-nucleoside reverse
transcriptaseinhibitors (NNRTIs)
Nevirapine, Efavirenz,
Delavirdine
c. Protease inhibitors Ritonavir,Atazanavir, Indinavir,
Nelfinavir
Saquinavir, Amprenavir,
Lopinavir
d. Entry (Fusion) inhibitorEnfuvirtide
e. CCR5 receptor inhibitor Maraviroc
f. Integraseinhibitor Raltegravir
13

14. Anti-Herpes virus
HerpesvirusisDNAvirus,itcausesvariousdiseasessuchas
coldsores,genitalherpes,chickenpox,shingles,eyediseases,
mononucleosis,Burkitt’slymphomaandKaposi’ssarcoma.
Nucleosideanalogueshavebeenparticularlyeffective
Egof drugs
Purine Antagonist:
Acyclovir, Vidarabine, Ganciclovir, Valacyclovir
Pyrimidine Antagonist
Cytarabine, Idoxuridine, Trifluorothymidine
Phosphorus Derivatives: Foscarnet
All these drugs are Inhibitors of viral DNA polymerase
14

15. Acyclovirwasdiscoveredandwas
introducedintothemarketin1981.
Acyclovirhasanucleoside-like
structureandcontainsthesame
nucleic acid base as
deoxyguanosine(GTP)
However,itlacksthecomplete
sugarring.
Invirallyinfectedcells,thedrugis
phosphorylatedinthreestagesto
formatriphosphatewhichisthe
activeagent.
soaciclovirisaprodrug
Acyclovir (Zovirax)
15
Active form of drug

16. Acyclovir -MOA
Step 1: Activation
Inhibits DNA-polymerase irreversibly
Acicloviris a selectively up taken by infected cells & converted to
the active triphosphate in infected cells. So it is prodrug
Viral thymidinekinase is 100 times more effective for converting
acyclovirto its monophosphatethan host cell thymidinekinase.
Therefore, An advantage is that Aciclovirdoesn’t enter into
uninfected human cells.
16

17. Acyclovir -MOA
Step 2: Incorporation into growing
DNA chain
Getsincorporatedin
viralDNA
Asthesugarunitis
incompleteandlacksthe
required-OHgroup
normallypresentat
position3′ofthesugar
ring,thenucleicacid
chaincannotextendany
further.Thusthedrugact
aschainterminator
17

18. Si
HN
Si
H
3C
CH
3
CH
3
CH
3
CH
3
hexamethyl disilazane
N
N N
H
N
OH
H
2N CH
3
N
N N
H
N
O
HN
Si
H
3C
CH
3
CH
3
Si
H
3C
CH
3
CH
3
H
2C
CH
2O
CH
2Cl
O
O
1-benzoyloxy-2-chloromethoxyethane
N
N N
N
O
HN
Si
H
3C
CH
3
CH
3
Si
H
3C
CH
3
CH
3
H
2C
CH
2O
CH
2
O
O
N
N N
N
OH
H
2N
H
2C
CH
2O
CH
2
OH
MEOH/NH3 Synthesis of acyclovir
Guanine
2-amino,6-hydroxr-9-(2-hydroxyethoxymethyl)-3H-purine
18

19. Theoralbioavailabilityofacyclovirisquitelow(15–30%).
Toovercomethis,variousprodrugsweredevelopedtoincreasewater
solubility.
Valaciclovirisanl-valylesterprodrugabsorbedfromthegutfarmore
effectivelythanacyclovir.Oncevalaciclovirisabsorbed,itishydrolysed
toacyclovirintheliverandgutwall.
Desciclovirisaprodrugofacyclovirwhichlacksthecarbonylgroupat
position6ofthepurineringandismorewatersoluble.
Inthebody,itismetabolisedbycellularxanthineoxidasetooxidizes
the6-positiontogiveacyclovir.
19

20. Someviruseslacktheenzymethymidinekinase.
Asaresult,phosphorylationfailstotakeplace.
Cidofovirwasdesignedtocombatthisproblem
Itisananalogueofdeoxycytidine5-monophosphatewherethe
sugarandphosphategroupshavebeenreplacedbyanacyclic
groupandaphosphonomethylenegroup.
Thelattergroupactsasabioisostereforthephosphate
Susceptible for
enzymatic hydrolysis
Resistant for enzymatic
hydrolysis
20

21. The following drugs arephosphorylated equally by viral&
cellular thymidinekinase, so there is less selectivity and more
toxicity.
Foscarnethas difficulty in crossing cell membrane due to high
charge
21
Idoxuridine Trifluridine Vidarabine
Foscarnet

22. Foscarnet(phosphonomethanoicacid)
22
Foscarnetis a structural mimic of the
anionpyrophosphatethat selectively inhibits the
pyrophosphate binding site on viralDNA
polymerasesatconcentrationsthat do not affect human
DNA polymerases.
Unlike acyclovir and ganciclovir, foscarnetis not activated
by viral protein kinases, making it useful in acyclovir-or
ganciclovir-resistant HSV and CMV infections
Foscarnethas difficulty incrossing cell membrane due to
high charge.
Nephrotoxicity, Electrolytedisturbances,
Genitalulceration
CNS —paresthesia,irritabilityandhallucinations.

23. Therapeutic uses of Acyclovir
Acyclovir is the drug of choice for:
HSV Genital infections,encephalitis &
Varicella zoster virus (VZV)
HSV infections in immunocompromised patient
Ganciclovir is the drug of choice for:
CMV retinitis in immunocompromised patient
Prevention of CMV disease in transplant patients
Cytomegalovirus retinitis, also known asCMV retinitis, is an
inflammation of the retina of the eye that can lead to blindness.
Caused by cytomegalovirus, it occurs predominantly in people
whose immune system has been compromised, 15-40% of those
infected with AIDS.
Valacicloviris a valineprodrug of aciclovirand is particularly
useful in the treatment of VZV infections.
23
CMV retinitis

24. Cidofovir (a nucleotide analog of cytosine) & foscarnet
•It is approved for the treatment of CMV retinitis in
immuno compromised patients.
Vidarabinis used in Herpes Simplex Virus Kerato-
conjunctivitis.
Therapeutic uses Conti……
24
Herpes Simplex

25. Adamantanes
Amantadine and Rimantadine is used as Anti-influenza
virus
AmantadineandRimantadinearebothdrugsthatinterferewith
penetrationofhostcellsbyvirusesandblockearlystage
replication.
Amantadine1-adamantanaminehydrochloride(Symmetrel).
Rimantadine,itismethyl-1-adamantanederivative
Theseareunusualcagedtricyclicamineswiththefollowing
structures:
25

26. Amantadinehasbeenusedforyearsasa
treatmentforParkinsondisease.
Bothoftheseagentswillspecificallyinhibit
replicationoftheinfluenzatypeAvirusesatlow
concentrations.
Rimantadineisgenerally4to10timesmore
active,lesstoxicthanamantadine.
Theadamantanamineshavetwomechanismsin
common:
(a)theyinhibitanearlystepinviralreplication,most
likelyviraluncoating,and
(b)insomestrains,theyaffectbyinterferingwith
haemagglutinin(Aviralprotein,whichcauses
haemagglutination)processing.
26

27. Synthesis of Amantadine
27
Adamantane 1-bromo
adamantane
1-acetylamino
adamantane
Amantadine
Ritter Reaction:
Acetonitrile in
presence of
sulphuric acid

28. Vidarabine
Itisadenosinederivative
Chemically,vidarabine(Vira-A),is9—D
arabinofuranosyladenine.
Introducedin1960asacandidate
anticanceragent,
vidarabinewasfoundtohavebroad-
spectrumactivityagainstDNAviruses.
Vidarabineisalsousedtotreatherpes
zosterinAIDSpatients
A3%ophthalmicointmentVira-A
isusedinthetreatmentofacute
keratoconjunctivitisandrecurrent
superficialkeratitiscausedby
HSV-1andHSV-2.
28

29. HSVencephalitis.
Althoughtheagentwasinitiallyprepared
chemically,itisnowobtainedbyfermentationwith
strainsofStreptomycesantibioticus.
Mechanism of Action
Theantiviralactionofvidarabineiscompletely
confinedtoDNAviruses.
VidarabineinhibitsviralDNAsynthesisbyblocking
viralDNApolymerase.
Vidarabinetriphosphateisalsoincorporatedinto
cellularandviralDNA,whereitactsasachain
terminator.
29

30. Anti-HIV Drugs
30
Thered ribbon, as an awarenessribbon, is
used as thesymbol forthe solidarityofpeople
living withHIV/AIDS, andforthe awareness and
preventionofdrug abuse and drunk driving.

31. HIV
HIV = Human
Immunodeficiency Virus
(Causative organism)
Destroys CD
4cells (T-cells
and macrophages)
AIDS = Acquired
Immunodeficiency Virus
(Disease)(~10 years after
infection)
HIV-1 = Most common
HIV-2 = relatively
uncommon and less infectious
*http://en.wikipedia.org/wiki/Aids#Diagnosis
31

32. When a person with HIV is considered to have
progressed to AIDS ?
ApersonwithHIVisconsideredtohave
progressedtoAIDSwhen:
ThenumberoftheirCD4cellsfallsbelow200cells
percubicmillimeterofblood(200cells/mm3).
(Inahealthyimmunesystem,CD4countsare
between500and1,600cells/mm3.)OR
Theydeveloponeormoreopportunistic
infectionsregardlessoftheirCD4count.
32

33. The Life Cycle of HIV
•Free Virus
•Binding and Fusion
•Infection
•Reverse Transcription
•Integration
•Transcription
•Assembly
•Budding
•Maturation
33

34. 34
HIV surface proteingp120
co-receptor gp41
Thebindingofgp120to
acoreceptoreitherCCR5orCXCR4.
Virus penetration of thecell membraneby
gp41: fusion.
Binding, fusion, entry sequence

35. Binding, fusion, entry sequence
HIVentryintoahumancellrequiresthefollowing
stepsinsequence.
ThebindingofHIVsurfaceproteingp120totheCD4
receptor(Host)
Aconformationalchangeingp120,whichboth
increasesitsaffinityforaco-receptorandexposesgp41
Thebindingofgp120toaco-receptoreitherCCR5or
CXCR4
Thepenetrationofthecellmembranebygp41,which
approximatesthemembraneofHIVandtheTcelland
promotestheirfusion.
Theentryoftheviralcoreintothecell
Entryinhibitorsworkbyinterferingwithoneaspectof
thisprocess.
35

36. Reverse transcriptase/DNA polymerase
RetrovirusespossessDNApolymerase(Reverse
transcriptase)thatdirectsthesynthesisofa
DNAcopiesfromtheviralRNA.
TheformedDNAisduplicated,circularized,and
incorporatedintotheDNAofaninfectedcell.
RNA
DNA
Reverse
transcriptase
/DNA
Polymerase
36

37. Classification of Anti-drugs
HAART
Entry Inhibitors
Reverse
Transcriptase
Inhibitors (RTIs)
Protease
Inhibitors
Nucleoside/
Nucleotide RTIs
(NRTIs)
Non-Nucleoside
RTIs (NNRTIs)
(Highly Active Anti Retroviral Therapy)
37

38. Anti HIV DRUGS
i)Nucleoside Reverse Transcriptase Inhibitors(NRTIs)
NRTIs block reverse transcriptase, an enzymeHIV
needs to make copies of itself.
Zidovudine
Lamivudine
Stavudine
Abacavir
Didanosine
Tenofovir (component of atripla)
Emtricitabine (component of atripla)
38

39. ii)Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
They don't have Nucleic acid structure and target reverse
transcriptase but act different way as NRTIs
Efavirenz, (component of atripla)
Nevirapine,
Rilpivirine
iii) Protease Inhibitors (PIs), which target an HIV protein
called protease. (maturing of proteins)
Darunavir,
Indinavir,
Nelfinavir,
Ritonavir, (now used in treatment of corona virus)
Saquinavir
39

40. iv)FusioninhibitorsblockHIVfromenteringthe
CD4cellsoftheimmunesystem/EntryInhibitors
Enfuvirtide
Maraviroc
vi)Integrase inhibitors block HIV integrase, an
enzyme HIV needs to make copies of itself.
Dolutegravir,
Elvitegravir
Raltegravir
40

41. Fusion Inhibitors/Entry Inhibitors
Fusion inhibitors block the
HIV envelope from merging
with the host CD4 cell
membrane (fusion).
This prevents HIV from
entering the CD4 cell.
Eg of drugs
Enfuvirtide
Maraviroc
41

42. Maraviroc (Selzentry)
1
st
oral entry inhibitor
Maraviroc works by targetingCCR5, a
co-receptor located on human helper
T-cells.
Maraviroc can cause serious, life-
threatening side effects. These include
liver problems, skin reactions, and
allergic reactions
42
It also appeared to reducegraft-versus-host diseasein
patients treated withallogeneicbone marrow
transplantationforleukemia,

43. Fusion Inhibitors/Entry Inhibitors
(Enfuviritide)
43
Enfuvirtide is apeptide drug that must be injectedand acts by
interacting with the N-terminal heptad repeat of gp41of HIV to
form aninactive hetero six-helix bundle, therefore preventing
infection of host cells

44. Reverse Transcriptase Inhibitors: NRTIs
Tenofovir
•Competitive inhibitors
•No effect on host enzymes
44
Zidovudine Stavudine
Emtricitabine

45. TheenzymeReverseTranscriptaseisuniquetoHIV,it
servesasanidealdrugtarget.
Thesedrugshavenucleoside-likestructures.
Thesedrugsarephosphorylatedbythreecellular
enzymes(notviralkinases)toformanactivenucleotide
triphosphate.
Zidovudinewasdevelopedoriginallyasananticancer
agentbutwasthefirstdrugtobeapprovedforuseinthe
treatmentofAIDS.
Itisananalogueofdeoxythymidinewherethesugar3′-
OHgrouphasbeenreplacedbyanazidogroup.
Onconversiontothetriphosphate,itinhibitRtase.
Since the sugar unit has an azidesubstituent at the 3′
position of thesugar ring, the nucleic acid chain cannot be
extended any further
45

46. Zidovudine
3’-azido-3’-deoxythymidine or AZT, is an analog of
thymidine that possesses antiviral activity against HIV-1,
HIV-2.
Lamivudine & Emtricitabine are deoxycytidine where the
3’ carbon has been replaced by Sulphur
46
Thymidine
Natural
nucleoside

47. TheclinicallyusefulNRTIsusedagainstHIVand/or
hepatitisBincludeabacavir(theonlyguanosineanalogue),
Stavudine(thymidineanalogue)andzalcitabine(cytosine)
NRTIshavegoodoralbioavailability,arebound
minimallytoplasmaproteins,andareexcreted
throughthekidneys.
47
Abacavir/Ziagen(ABC)
Stavudine/Zerit(d4T)
Thymine
zalcitabine/HIVID(ddC)
Cytosine
Guanosine

48. Tenofovir
ItisamedicationusedtotreatchronichepatitisBandtoprevent
andtreatHIV/AIDS.
ItisusedforpreventionofHIV/AIDSamongthoseathighrisk
beforeexposure,andafteraneedlestickinjuryorotherpotential
exposure.
Itisoftenrecommendedduringpregnancyandappearstobesafe.
Itisanucleotidereversetranscriptaseinhibitorandworksby
decreasingtheabilityofthevirusestoreplicate.
48
9-(2-Phosphonyl-methoxypropyly)adenine (PMPA)
Tenofovir can be used for HIV
prevention in people who are at high
risk for infection through sexual
transmission or injecting drug
use.

49. Synthesis of Zidovudine
49

50. Reverse Transcriptase Inhibitors: NNRTIs
TheNNRTIsaregenerallyhydrophobic
moleculesthatbindtoanallostericbindingsite
whichishydrophobicinnature.
Sincetheallostericbindingsiteisseparatefrom
thesubstratebindingsite,
theNNRTIsarenon-competitive,reversible
inhibitors.Theyinclude
First-generationNNRTIs
NevirapineandDelavirdine
Second-generationNNRTIs
Efavirenz,Etravirine,Rilpivirine
50

51. Reverse Transcriptase Inhibitors: NNRTIs
Nevirapine Delavirdine
Efavirenz (component of
atripla)
•Only active against HIV-1
Thesedrugsarevulnerabletoresistance,rapidresistance
emergesasaresultofmutationsintheNNRTIbindingsite—the
mostcommonbeingthereplacementofLys-103withasparagine.
ThismutationiscalledK103Nandisdefinedasapanclass
resistancemutation.
Theresistanceproblemcanbecounteredbycombiningan
NNRTIwithanNRTIfromthestartoftreatment,asthebinding
sitesaredistinct.
51

52. 52

53. Protease Inhibitors (PIs)
HIVproteaseisanenzymethatcatalyzeprocess
ofmaturationandpropagationofnewvirus.
Inhibitionofthispost-translationstepleadsto
totalarrestofviralmaturation&blockvirulence
propertyofthevirus.
HIVPIsaredesignedtomimicthetransitionstate
ofhydrolysisattheactivesiteofproteinsofHIV
virus;sothesedrugsarecalledastransitionstate
inhibitors.
53

54. Hydrolysisofapeptidebondproceedsthrougha
transitionstatethatissp3hybridizedand,hence,
tetrahedral.
Theanaloginhibitorspossessapreexistingsp3
hybridizedcenterthatwillbedrawnintotheactivesite
butstabletohydrolysis.
So blocking viral post translation processes, maturation
step & prevent the spread of cellular infection.
Saquinavir (Invirase), Indinavir (Crixivan), Ritonavir
(Norvir), Nelfinavir (Viracept), Amprenavir (Agenerase)
have been approved for the treatment of HIV-infected
patients.
54

55. Fosamprenavir
Increasedwatersolubilityandimproved
oralbioavailability
Metabolizedtoformamprenavir,which
istheactiveingredient
Becauseitmustbemetabolized,itis
timereleasedandrequireslessdosages
(4insteadof16pillsperday)
PossibleSideEffects:
Nausea,Vomiting,Diarrhea,Loose
Stool,Hyperglycemia,andFatigue
55
Fosamprenaviris a drug for the treatment of HIV infections.
It is a pro-drugof drug Amprenavir.

56. Atripla
Aone-pill,once-a-dayHIV-1treatment.
ATRIPLA
®
isaprescriptionmedicationthatcanbeusedaloneasa
completeregimen,orincombinationwithotheranti-HIV-
1medicines,totreatHIV-1inpatientswhoweighatleast40
kg(88lbs).
Efavirenz(NNRTIs)/Emtricitabine/Tenofovir(both NRTIs)
56

57. Composition of atripla
57
Efavirenz
Tenofovir disoproxil
Emtricitabine

58. Thank You
58