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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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
2The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
3The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
4The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
5The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
6The screen versions of these slides have full details of copyright and acknowledgements
16
Truvada®
This was the very first compound ever approved by the FDA
for the prevention of HIV infections
Tenofovir disoproxil fumarate (TDF)Fumarate salt of bis(isopropoxycarbonyloxymethyl) ester
of (R)-9-(2-phosphonylmethoxypropyl)adenine bis(POC)-PMPAViread®
(-)-FTCEmtricitabine
(-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine Emtriva®
17
Atripla®
Tenofovir disoproxil fumarate (TDF)Fumarate salt of bis(isopropoxycarbonyloxymethyl) ester
of (R)-9-(2-phosphonylmethoxypropyl)adenine bis(POC)-PMPAViread®
(-)-FTCEmtricitabine
(-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine Emtriva®
EfavirenzSustiva®, Stocrin®
18
Complera®/Eviplera®
Tenofovir disoproxil fumarate (TDF)Fumarate salt of bis(isopropoxycarbonyloxymethyl) ester
of (R)-9-(2-phosphonylmethoxypropyl)adenine bis(POC)-PMPAViread®
(-)-FTCEmtricitabine
(-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine Emtriva®
Rilpivirine (TMC278, R278474)Edurant®
Rilpivirine can be dosed at a much lower dose than Efavirenz and it has
much less side effects
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
7The screen versions of these slides have full details of copyright and acknowledgements
19
StribildTM
Cobicistat
Quad
Tenofovir disoproxil fumarate (TDF)Fumarate salt of bis(isopropoxycarbonyloxymethyl) ester
of (R)-9-(2-phosphonylmethoxypropyl)adenine bis(POC)-PMPAViread®
(-)-FTCEmtricitabine
(-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine Emtriva®
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)
(-)-FTCEmtricitabine
(-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine Emtriva®
Cobicistat
SN
OHNH2
O O
HN
OPh
O
O
O
H
H
H
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
8The screen versions of these slides have full details of copyright and acknowledgements
22
Another planned quad
GS-7340
(-)-FTCEmtricitabine
(-)-β-L-3’-thia-2’,3’-dideoxy-5-fluorocytidine Emtriva®
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
9The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
10The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
11The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
12The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
13The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
14The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
15The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
16The screen versions of these slides have full details of copyright and acknowledgements
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)
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
17The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
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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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
19The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
20The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
21The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
22The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
23The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
24The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
25The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
26The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
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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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
28The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
29The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
30The screen versions of these slides have full details of copyright and acknowledgements
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)
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
31The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
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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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
33The screen versions of these slides have full details of copyright and acknowledgements
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
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
34The screen versions of these slides have full details of copyright and acknowledgements
100
101101
102Henri Joseph Rega
(1690 ─ 1754)
Current Trends in Antiviral Drug DevelopmentProf. Erik de Clercq
35The screen versions of these slides have full details of copyright and acknowledgements
103Pieter De Somer
(1917 – 1985)
104
105
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