Current Trends in Antiviral Drug Development Prof. Erik de ... · Current Trends in Antiviral Drug Development Prof. Erik de Clercq 4 The screen versions of these slides have full

Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq

1The screen versions of these slides have full details of copyright and acknowledgements

1

Current Trends in Antiviral Drug Development

Prof. Erik De ClercqRega Institute for Medical Research

Faculty of Medicine KU Leuven, Belgium

2

Introduction

3

IDU

5-Iodo-2’-deoxyuridine

IUDR

Idoxuridine

Herpid®, Stoxil®

HN

N

OHO

HO

IO

O

IDU



4

TFT5-Trifluoromethyl-2’-deoxyuridine

TrifluorothymidineTrifluridineViroptic®

HN

N

OHO

HO

O

O

F

FF

TFT

5

MethisazoneN-Methylisatin β-thiosemicarbazone

Marboran®

N O

N NH C NH2

S

CH3

Methisazone

6

Amantadine

Amantadine (HCl)Symmetrel®, Mantadix®, Amantan®

NH2•HCl



7

Ribavirin

Ribavirin1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide

Virazole®, Virazid®, Viramid®

OHO

HO OH

H2N

N

N

N

O

8

ArabinosyladenineAra-A

VidarabineVira-A®

N

N

N

N

NH2

OHO

OH

HO

Ara-A

9

HIV



10

Replicative cycle of HIV

De Clercq, Nature Rev. Drug Discovery, 1, 13-25 (2002)

RNA

EnvelopeCapsid coreReversetranscriptase

Reversetranscription

Viral Absorption

Budding

Receptor and co-receptor proteins

Virus-cell fusion

Viral proteins andRNA assemble at

the cell membrane

11

Suramin (hexasodium salt)Moranyl, Naganol, Antrypol, Germanin, Bayer 205

O

NH

NHO

O

NH

NH

OHN

NH

-O3S

-O3S SO3-

O

-O3S SO3-

SO3-

CH3

H3C

Na+Na+

Na+ Na+ Na+ Na+

Suramin

12

Zidovudine

Zidovudine3’-Azido-2’,3’-dideoxythymidine, azidothymidine (AZT)

Retrovir®

HN

N

OCH3

O

OHO

N3



13

(-)-FTCEmtricitabine

(-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine Emtriva®S

O

HO

N

N

NH2

O

F

Emtricitabine

14

Tenofovir disoproxil fumarate (TDF)Fumarate salt of bis(isopropoxycarbonyloxymethyl) ester

of (R)-9-(2-phosphonylmethoxypropyl)adeninebis(POC)-PMPA

Viread®

CH

HC

HOOC

COOH

N

N

N

N

P O

NH2

O OO

CH2OCOO

CH2OCO

O CH3

(CH3)2CH(CH3)2CH

TDF

15

NRTIs

NtRTIs

PIs

NNRTIs

CRIsFIs

INIs



16

Truvada®

This was the very first compound ever approved by the FDA

for the prevention of HIV infections


of (R)-9-(2-phosphonylmethoxypropyl)adenine bis(POC)-PMPAViread®


(-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine Emtriva®

17

Atripla®





EfavirenzSustiva®, Stocrin®

18

Complera®/Eviplera®





Rilpivirine (TMC278, R278474)Edurant®

Rilpivirine can be dosed at a much lower dose than Efavirenz and it has

much less side effects



19

StribildTM

Cobicistat

Quad





Elvitegravir(GS-9137, JTK-303)

20

GS-7340

Tenofovir(R)-PMPA

N

N

N

N

O P

CH3

NH2

OHOH

ON

N

N

N

O P

CH3

O

O

NH2

NH

O

O

H3C

GS-7340

21Darunavir (TMC-114)

Prezista®

GS-7340

Quad (planned)



Cobicistat

SN

OHNH2

O O

HN

OPh

O

O

O

H

H

H



22

Another planned quad

GS-7340



CobicistatElvitegravir

(GS-9137, JTK-303)

N

OH

OOF

C l

HOH

O

23RitonavirNorvir®

Cobicistat

H

H

HS

NN

S

CH3

N N

O

N

OH

N O

OCH3H3C

O

H3CCH3

24

HCV

• The Hepatitis C virus can be eradicated from the organism, while HIV eradication is not possible

• HCV is an RNA virus and whereas HIV behaves as a DNA virus in the sense that through the reverse transcriptase it is converted from RNA to DNA



25 Asselah & Marcellin. Liver Int. 32, Suppl. 1, 88-102 (2012)

Hepatitis C virus (HCV) genome and potential drug discovery targets

The HCV RNA genome serves as a template for viral replication and as a viral mRNA for viral production; It is translated into a polyprotein that is cleaved by proteases; All the HCV enzymes –NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RdRp – are essential for HCV replication, and are therefore potential drug discovery targets

26

Company TargetNS3/4A

Vertex Telaprevir (Incivek®)Merck Boceprevir (Victrelis®)Abbott ABT-450/rBoehringer-Ingelheim BI-201335Bristol-Myers Squibb Asunaprevir (BMS-650032)

Gilead GS-9256GS-9451

Roche Danoprevir (ITMN-191, RG7227)

Merck MK-5172Vaniprevir (MK-7009)

Achillion ACH-1625ACH-2684

Schering - Merck Narlaprevir (SCH 900518)Tibotec Simeprevir (TMC 435)

27

Telaprevir/Incivek®

N

N

O NH

O

HN

H3C CH3

N

O

CH3

H

H

NHO

H3CO

O

NH



28

Boceprevir/Victrelis®

O

HN

HN O

HN

OO

O

NH2

H

29

BMS-650032/Asunaprevir

NH

S

O

HN

O

HN

O

OO

O

O

NCl

OMe

O

30

GS-9256

F

F

NN

SHN

O

O

Cl

NHNO

O

HN P

OOH

O

O



31

GS-9451

NN

SHNO

O

Cl

N

O

N HN

O

O

OHHN

OO

O

32

NHN

O

O

NH

O

O

ON

O F

NH

S

O

O

Danoprevir/ITMN-191/RG7227

33

N

ONH

N

O

O

H

OO

H HN

OH

NHH

SO OO

Vaniprevir/MK-7009



34

O

HN

HN

SO

ON

OO

HN

O

HN

O

Narlaprevir/SCH900518

35

NN

S

O

O

N

HN

O

NH

SO O

OO

Simeprevir/TMC435

36

Company TargetNS5A

Abbott ABT-267

Bristol-Myers Squibb Daclatasvir (BMS-790052)

Gilead GS-5885Achillion ACH-2928

Presidio Pharmaceuticals PPI-1301PPI-461

Atra Zeneca AZD-7295



37

N

HNN

NH

N

NO

O

H3CO2CHN

NHCO2CH3

Daclatasvir/BMS-790052

38

Company TargetNS5B (nucleoside type)

Bristol-Myers Squibb INX-189Gilead Sofosbuvir (GS-7977)

Roche Mericitabine (RG7128, RO5024048)

BioCryst BCX-5191Idenix IDX-184

Alios Biopharma ALS-2200ALS-2158

Medivir (collab. with Tibotec) TMC 649128

39

HO

O

F

NNH

OPNH

O

O

O

O

O

O

Sofosbuvir/GS-7977



40

O

O

F

NN

O

O

NH2

O

O

Mericitabine/RG7128/RO5024048

41

Company TargetNS5B (non-nucleoside type)

Vertex VX-222

Abbott ABT-072ABT-333

Boehringer-Ingelheim BI-207127Gilead Tegobuvir (GS-9190)Anadys Setrobuvir (ANA-598)Pfizer Filibuvir (PF-868554)

ViroChem Pharma VCH-916VCH-759

42

VX-222

N

O

OH

S OHO



43

BI 201335

NN

SHNO

O

NNH

O

O

Br

O

NH

OO

OH

O

44

Tegobuvir/GS-9190

NN

N

N

N

F

F

FF

F

F

F

45

Setrobuvir/ANA-598

N

NS

HN

NH

S

F

H

HOH

O O

OO

O



46

Filibuvir/PF-868554

N

O O

N

NN

N

OH

47VCH-759

VCH-916

COOKO

N

O

S

COONaO

N

OH

S

48

Company OtherNovartis Alisporivir (Debio 25)Santaris MiravirsenITherX ITX5061

Perigrine BavituximabClemizole

Gilead GS-9620 (TLR7 agonist)Pfizer PF-4878691 (TLR7 agonist)



49

Alisporivir

CH3

C3

O

N

CH3C5

NH

C4

O

H3C

H3C

CH3

C8

H3C CH3

NCH3C10

O

CH3H3C C11

N

O

C1

CH3

H3C

HO

H3C

O

C9

ON

CH3

NH3C

O

NHH3C

C7O

NHH3C

C6O

CH3

N O

N

OC2

H3CCH3

CH3CH3

CH

H3C

CH3

NH

50

NS3/4Aproteaseinhibitors

NS5Ainhibitors

Nucleos(t)ideNS5B

polymeraseinhibitors

Non-nucleosideNS5B polymerase

inhibitors

51

Daclatasvir (BMS-790052) + Sofosbuvir (GS-7977) +/− Ribavirin

Ritonavir-boosted ABT-450 + ABT-333 + Ribavirin

Ritonavir-boosted ABT-450 + ABT-072 + Ribavirin

Daclatasvir (BMS-790052) + Asunaprevir (BMS-650032)

BI 201335 + BI 207127 + Ribavirin

Ritonavir-boosted Danoprevir (RG7227) + Mericitabine (RG7128) +/−Ribavirin

Incivek® (Telaprevir) + VX-222

GS-9256 + Tegobuvir (GS-9190) +/− Ribavirin

GS-9451 + GS-5885 + Tegobuvir (GS-9190) +/- Ribavirin

Simeprevir (TMC435) + Daclatasvir (BMS-790052)

Victrelis® (Boceprevir) + Mericitabine (RG7128) + Peg-IFN/Ribavirin

Chatel-Chaix et al., Curr. Opin. Virol., 2(5), 588-598 (2012)

Phase II DAA-based combination clinical trials



52

HSV

53

Acyclovir, Aciclovir9-(2-Hydroxyethoxymethyl)guanine

AcycloguanosineZovirax®

HN

N

N

N

O

H2N

OHO

54

ValaciclovirL-Valine ester of 9-(2-hydroxyethoxymethyl)guanine

Valtrex®, Zelitrex®

HN

N

N

N

O

H2N

OO

OH3C

NH2H3C



55

FamciclovirDiacetyl 6-deoxy-9-(4-hydroxy-3-hydroxymethyl-but-1-yl)guanine

Famvir®

N

N

N

NH2N

O

OH3C

O CH3

O

PenciclovirDenavir®, Vectavir®

HN

N

N

N

O

H2N

HO

OH

56Crumpacker & Schaffer. Nat. Med., 8, 327-328 (2002)

HSV DNA synthesis

The helicase−primase complex, consisting of viral proteins UL5, -8 and -52, unwinds HSV DNA at the replication fork and primes both lagging-strand and leading-strand DNA synthesis;The single-stranded DNA binding protein, ICP8, binds to single-stranded template DNA;HSV DNA polymerase and its accessory protein, UL42, promote leading- and lagging-strand DNA synthesis; The arrows indicate the direction of movement of the DNA replication proteins

57

AIC316(BAY 57-1293)

Pritelivir

N O

N

CH3

N

SS NH2

O

O

CH3



58

VZV

59

BVDU(E)-5-(2-Bromovinyl)-2’-deoxyuridine

BrivudinZostex®, Brivirac®, Zerpex®

HN

N

OHO

HO

O

O

C CH

BrH

60

Degradation of BVDU to BVU by thymidine phosphorylase and inhibition of the degradation of 5-fluorouracil by BVU

HN

NO

C C

H Br

H

O

H

BVDU

Thymidine phosphorylase

H O

HN

N

C

O

O

HO

O

C

H

H

Br

+ Pi BVU + O

HO

HO O P

2’-Deoxyribose-1-phosphate

5-Fluorouracil

Dihydrothyminedehydrogenase

HN

NO

O

F

H

HN

NO

O

F

H

BVU

5-Fluorodihydrouracil



61Cf 1743 FV-100

(Valine ester of Cf 1743)

H2N

H 3C

N

NO

O

O

OH

OCOCH

CHCH3

N

NO

O

O

OH

HO

Cf 1743 and FV-100

62

ASP2151

HN

O

N

SN

O N

O

O

O

63

HCMV



64

GanciclovirCymevene®, Cytovene®

ValganciclovirL-Valine ester of 9-(1,3-dihydroxy-

2-propoxymethyl)guanineValcyte®

HN

N

N

N

O

H2N

OO

OH3C

NH2H3C

OH

HN

N

N

N

O

H2N

OHO

OH

65

Phosphonoformic acidPFA

FoscarnetFoscavir®

PC

HO

HO

O

OH

O

Foscarnet

66

(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosineHPMPCCidofovirVistide®

PO

HO CH2

OHO

CH

CH2OH

N

N

CH2

NH2

O

Officially approved for use for CMV retinitis in AIDS patients



67

Maribavir

1263W94

1-(β-L-Ribofuranosyl)-2-isopropylamino-5,6-dichlorobenzimidazole

N

N

Cl

Cl

NH

OOH

OHHO

CH3

CH3

68

AIC246Letermovir

HO

O

N

N NN

O

F O

CF3

69

Poxviruses



70Stittelaar et al., Nature, 439, 745-748 (2006)

Kaplan–Meier plot showing the effect of different post-exposure treatments on the survival of monkeys infected with monkeypox virus

Survival expressed as percentages after intratracheal MPXV infection; After virus exposure, macaques were sham-treated (group I), vaccinated with smallpox vaccine Elstree-RIVM (group II), treated with 5 doses of cidofovir (group III), with 6 doses of cidofovir (group IV), with 5 doses of HPMPO-DAPy (group V) or with 6 doses of HPMPO-DAPy (group VI)

71

HDP-cidofovir

CMX001

N

N

NH2

O

O P O(CH2)3O(CH2)15CH3

O

OH

HO

72

H

OHN

FF F

NO

O

HH

H

ST-246



73

HBV

74

• (Pegylated) interferon-α

• Lamivudine

• Adefovir dipivoxil

• Entecavir

• Telbuvidin

• Tenofovir disoproxil fumarate (TDF)

Anti-HBV agents

75

Lamivudine

2’,3’-Dideoxy-3’-thiacytidine3TC

Epivir®

S

O

HO

NH2

O

N

N



76

Adefovir dipivoxil

Bis(pivaloyloxymethyl)ester of 9-(2-phosphonylmethoxyethyl)adenine, bis(POM)PMEA

Hepsera®

N

N

N

N

OPOO

O

CH2

CH2

OC(CH3)3C

OC(CH3)3C

O

O

NH2

77

EntecavirBaraclude®

N

NH

N

N

O

NH2

HO

HO

H2C

78

L-dTβ-L-thymidine

TelbivudineTyzeka®, Sebivo®

HN

N

O

O

O

OH

OH

CH3



79

Tenofovir disoproxil fumarate (TDF)

Fumarate salt of bis(isopropoxycarbonyloxymethyl) ester of (R)-9-(2-phosphonylmethoxypropyl)adenine

bis(POC)-PMPA

Viread®

CH

HC

HOOC

COOH

N

N

N

N

P O

NH2

O O

O

CH2OCO

O

CH2OCO

O CH3

( CH3)2CH( CH3)2CH

80

Patients with chronic Hepatitis Bvirologic response up to Year 4

Lee et al., AASLD, 2010; Lampart et al., AASLD, 2010

% P

atie

nts

HB

V D

NA

< 40

0 co

pies

/mL

Open labelDouble-Blind

Study Week

81

Influenza virus



82De Clercq. Nat. Rev. Drug Discov., 5, 1015-1025 (2006)

Inhibition of the influenza-virus replication cycle by antiviral agents

83

ZanamivirRelenza®

OHN

HO

HO

NH

OH

NH2

NH

CH3

O

OHO

84

Oseltamivir (ethyl ester)Tamiflu®

HN

O

NH2CH3

O

OO CH2

CH3



85

86

RWJ-270201Peramivir

C

O

OH

OH

HN

H2N NH

HN

O

87

Laninamivir octanoateCS-8958Inavir®

H3C

O

NH

HN

O

OH

OCH3O

H2N

CO2H

NH

HH3C

O



88

N

NF

OH

CONH2

Favipiravir (T-705)

89Furuta et al., Antimicrob. Agents Chemother., 49: 981-986 (2005)

Phosphoribosyl- transferase

90

Enveloped viruses(including filo-, bunya- and flaviviruses)



91Neplanocin A (X = N)

3-Deazaneplanocin A (X = CH)

HO OH

HO

N

N

N

X

NH2

Neplanocin A

92

dUY11

St. Vincent et al., Proc. Natl. Acad. Sci. USA, 107, 17339-17344(2010)

HN

N

O

O

O

HO

HO

93

LJ-001

Wolf et al., Proc. Natl. Acad. Sci. USA, 107, 3157-3162 (2010)

O

S

N

S

O



94Aman et al., Antiviral Res. 83, 245-251 (2009)

FGI-106

NN

NHN

HN N

95

Picornaviruses

96

Pleconaril

O

CH3

H3CN

NO

FF

F

ON

H3C



97

Pirodavir(R77975)

NNN

OCOOEtH3C

98

Rupintrivir (AG-7088)

NH

O

NH

O

F

NH

NO

O

CO2Et

O

99

TBZE-029

N

N

S

F

F

F3C



100

101101

102Henri Joseph Rega

(1690 ─ 1754)



103Pieter De Somer

(1917 – 1985)

104

105

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Current Trends in Antiviral Drug Development Prof. Erik de ... · Current Trends in Antiviral Drug Development Prof. Erik de Clercq 4 The screen versions of these slides have full