Download presentation as
Transcript of Download presentation as
![Page 1: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/1.jpg)
Erik DE CLERCQRega Institute for Medical Research, K.U.Leuven
B-3000 Leuven, Belgium
ANTI-HERPESVIRUS THERAPIES:BASIC STRATEGIES AND APPLICATIONS
![Page 2: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/2.jpg)
HerpesviridaeHuman herpesviruses (HHV)
HHV-1: Herpes simplex virus type 1 (HSV-1)HHV-2: Herpes simplex virus type 2 (HSV-2)HHV-3: Varicella-zoster virus (VZV)HHV-4: Epstein-Barr virus (EBV)HHV-5: Human cytomegalovirus (HCMV)HHV-6: Human herpes simplex virus type 6 (HSV-6)HHV-7: Human herpes simplex virus type 7 (HSV-7)HHV-8: Kaposi’s sarcoma herpesvirus (KSHV)
![Page 3: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/3.jpg)
OHO
O
H2N N
N
N
HN
Acyclovir, Aciclovir (ACV), Acycloguanosine9-[(2-Hydroxyethoxy)methyl]guanine
Zovirax®
![Page 4: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/4.jpg)
HN
N
N
N
O
H2N
OHO
HN
N
N
N
O
H2N
OOCOCHH2N
CHH3C CH3
HN
N
N
N
O
H2N
OOCOCH2H2N
HN
N
N
N
O
H2N
OOCOCH
CH3
H2N
Acyclovir Acyclovir valyl esterValaciclovir
Acyclovir glycyl ester Acyclovir alanyl ester
![Page 5: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/5.jpg)
ValaciclovirValine ester of acyclovir
Valtrex®, Zelitrex®
O
O
H2N N
N
N
HN
OC
OHCH2N
CHH3C CH3
![Page 6: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/6.jpg)
Antiviral activity spectrum of valaciclovir(acyclovir)
Herpesviridae! Herpes simplex virus type 1 (HSV-1)! Herpes simplex virus type 2 (HSV-2)! Varicella-zoster virus (VZV)! Epstein-Barr virus (EBV)" Human cytomegalovirus (HCMV)" Human herpesvirus type 6 (HHV-6)" Human herpesvirus type 7 (HHV-7)" Human herpesvirus type 8 (HHV-8)" Thymidine kinase-deficient HSV (TK- HSV)" Thymidine kinase-deficient VZV (TK- VZV)
![Page 7: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/7.jpg)
Major clinical indications of valaciclovir
Systemic (oral) treatment of HSV and VZV infections:
• primary and recurrent genital herpes, mucocutaneousHSV-1 and HSV-2 infections in immuno-compromised and –competent patients
• varicella-zoster in immuno-compromised and –competent patients
![Page 8: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/8.jpg)
OH
N
N
N
HN
H2N
HO
O
N
N
N
N
H2N
H3C O
O
OH3C
O
Famciclovir Penciclovir Famvir®
![Page 9: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/9.jpg)
OH
HO
N
N
N
NH2N
OH
HO
HN
N
N
NH2N
O
Xanthineoxidase
Xanthineoxidase
Xanthineoxidase
Esterase
EsteraseEsterase
Esterase
OH
OH3C
O
HN
N
N
NH2N
O
OH
OH3C
O
N
N
N
NH2N
O
O
H3C
O
H3C
O
N
N
N
NH2N
O
O
H3C
O
H3C
O
HN
N
N
NH2N
O
![Page 10: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/10.jpg)
Intravenous penciclovir versus acyclovir in the treatment of HSV infections in immunocompromised patients
Lazarus et al., Antimicrob. Agents Chemother. 43: 1192-1197 (1999)
Kaplan-Meier plot of time to healing of lesions for penciclovir at 5 mg/kg q12 h(long-dashed line), penciclovir at 5 mg/kg q8h (short-dashed line), and acyclovir at 5 mg/kg q8h (solid line)
![Page 11: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/11.jpg)
O
OH
N
N
N
HN
H2N
HO
O
Ganciclovir (GCV)9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG)
Cymevene®, Cytovene®
![Page 12: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/12.jpg)
ValganciclovirValcyte®
O
OH
N
N
N
HN
H2 N
O
O
C
OHCH2N
CHH3C CH3
![Page 13: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/13.jpg)
Nucleoside kinase
![Page 14: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/14.jpg)
3 Na+ P-O
O
O-
CO
O-
FoscarnetPhosphonoformate (trisodium salt)
PFAFoscavir®
![Page 15: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/15.jpg)
N
NH
N
N
O
NH2
OHO O
OH
HO
OH
HO
HO
OH
HO O
OH
HO HO
HO
HO
OHSynguanol A-5021 D/L-Cyclohexenyl guanine
Penciclovir Lobucavir Anhydrohexitol guanine
Acyclovir Ganciclovir H2GHO
OH
![Page 16: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/16.jpg)
Lobucavir
HO
OH
HN
N
N
N
O
H2N
![Page 17: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/17.jpg)
HN
N
N
N
O
H2N
OH
HO
(-) 2HM-HBGH2G
(-)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine
![Page 18: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/18.jpg)
N
N
N
N
NH2
HO N
NH
N
N
O
NH2HO
Synadenol Syngenol
Methylene cyclopropane nucleoside analogues
![Page 19: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/19.jpg)
D/L-Cyclohexenyl guanine
HO
OH
N
NH
N
N
O
NH2
![Page 20: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/20.jpg)
A-5021
N
NH
N
N
O
NH2
HO
HO
![Page 21: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/21.jpg)
N
NH
N
N
O
NH2
OH
HO
N
N
N
N
NH2
OH
HO
AV-038 A-5021
![Page 22: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/22.jpg)
Comparative potency of different antiherpetic compoundsagainst different herpesviruses
Compound 50% Effective concentrationEC50 (µM)
HSV-1 HSV-2 VZV HCMVAcyclovir +++ +++ ++ +Penciclovir +++ ++ ++ (+)Ganciclovir +++++ +++++ ++ ++Lobucavir ++++ ++++ +++ ++H2G ++++ ++++ ++++ (+)A-5021 ++++ +++ +++ +Synguanol + - + ++Anhydrohexitol G ++(+) +++(+) ++ ++D-Cyclohexenyl G ++++ +++ ++ ++L-Cyclohexenyl G +++(+) +++ ++ ++EC50 (µM)= 10-100 (+), 1-10 (++), 0.1-1 (+++), 0.01-0.1 (++++), 0.001-0.01 (+++++)
![Page 23: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/23.jpg)
N
N N
N
OHO
OH
H2N
S22422-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine
![Page 24: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/24.jpg)
Mycophenolic acid
OC
O
OH
CH3
OCH3
O CH3
OH
![Page 25: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/25.jpg)
Mycophenylate mofetil (Cellcept®)2-Morpholinoethyl ester of mycophenolic acid
OC
O
OH
CH3
OCH3
O CH3
ON
O
![Page 26: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/26.jpg)
MPA-IMPDH interactions
Sintchak et al., Cell 85: 921-930 (1996)
![Page 27: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/27.jpg)
XMP
GMP
GDP
GTP
RNAsynthesis
Deoxyguanosine
dGMP
dGDP
DNA synthesis
dGTP
Guanosine analogues
dGMP analogues
dGDP analogues
Phosphoribosylamine(PRA)
Mycophenolic acid
dGTP analogues
H2O + NAD+
NADH + H+
IMP dehydrogenase
IMP
![Page 28: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/28.jpg)
Virus Control 2.5 µg/ml MMF
1 µg/ml LBV 1 µg/ml LBV + 2.5 µg/ml MMF
Inhibitory effects of mycophenolate mofetil (MMF) and lobucavir (LBV)on cytopathicity of HCMV in human embryonic lung (HEL) cells
![Page 29: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/29.jpg)
Virus Control MMF
ACV MMF + ACV
Inhibitory effects of topical mycophenolate mofetil (MMF) 5% and topical acyclovir (ACV) 0.1% on HSV-1-induced lesions in hairless mice
![Page 30: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/30.jpg)
HN
N
O
O
I
OHO
OH
Idoxuridine5-iodo-2’-deoxyuridine (IDU)
Stoxil®
![Page 31: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/31.jpg)
OHO
OH
HN
N
O
O
CF3
Trifluridine, Trifluorothymidine (TFT)5-Trifluoromethyl-2’-deoxyuridine
Viroptic®, TFT-Ophthiol®
![Page 32: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/32.jpg)
O
HN
N
Br
O
O
HO
HO
Brivudin, Bromovinyldeoxyuridine(E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU)
Zostex®, Zonavir®
![Page 33: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/33.jpg)
De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002)
Antiviral activity spectrum of BVDU
![Page 34: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/34.jpg)
O
HN
N
Br
O
O
HO
HO
HOO
HN
N
Br
O
O
HO
HO
OH
HN
N
Br
O
O
HO
HO
BVaraU BVriboU C-BVDU
De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002)
![Page 35: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/35.jpg)
S
HN
N
Br
O
O
HO
HO O
N
N
Br
NH2
O
HO
HO
O
HOOH
HN
N
Br
O
O
S-BVDU BVDC L-BVDU
De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002)
![Page 36: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/36.jpg)
S-BVMU Triazolyl BVDC L-BVODDU derivative
S
HN
N
Br
O
O
HO
HO
O
O
HO
HN
N
Br
O
O
O
N
N
Br
O
HO
HO
N
N
N
De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002)
![Page 37: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/37.jpg)
BMS-181165 4’-methyl BVDU AV-100
OHO
OH
HN
N
Br
O
O
O
HN
N
Br
O
HO
HO
O
H3C
HN
N
Br
O
O
OH
HO
De Clercq, Recent Advances in Nucleosides: Chemistry and Chemotherapy, pp 433-454 (2002)
![Page 38: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/38.jpg)
Mechanism of action of BVDU
![Page 39: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/39.jpg)
HSV-1 dThd kinase DNA polymerase
BVDU BVDUMP BVDUDP BVDUTP DNA
BVDU BVDUMP
HSV-2 dThd kinase
![Page 40: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/40.jpg)
O
HN
N
C
O
HO
HO
O
CBr
H
H
HN
NH
C
O
O
CBr
H
H
O
HO
HO O
+ Pi BVU +Thymidine
phosphorylase
BVDU
HN
NH
O
F
O
HN
NH
O
F
ODihydrothymine dehydrogenase
BVU
5-Fluorouracil 5-Fluorodihydrouracil
P
![Page 41: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/41.jpg)
Major clinical indications of BVDU(Brivudin)
Topical: - herpetic keratitis (BVDU eyedrops)- herpes labialis (BVDU cream)
Systemic: - mucocutaneous HSV-1 and VZV infections(oral) - immunocompromised patients - immunocompetent patients
![Page 42: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/42.jpg)
Oral brivudin versus intravenous acyclovir in thetreatment of severe herpes zoster in cancer patients
BRIVUDIN: BVDU: (E)-5-(2-bromovinyl)-2’-deoxyuridineorally 125 mg x 4 per day for 5 days
ACYCLOVIR: ACV: 9-(2-hydroxyethoxymethyl)guanineintravenously 10 mg/kg x 3 per day for 5 days
Multicentered, double-blind, randomizedBVDU group (24 patients) also received placebo i.v.ACV group (23 patients) also received placebo p.o.
Wutzler et al., J. Med. Virol. 46: 252-257 (1995)
![Page 43: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/43.jpg)
Double-blind study BVDU versus ACV
Number of days following start of therapy
% P
atie
nts
with
new
ves
icle
s100
80
60
40
20
01 2 3 4 5 6 7
---- ACV (n = 23) — BVDU (n = 24)
![Page 44: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/44.jpg)
Current antiviral therapy for zoster
7 days1 x daily125 mgBrivudin oral
7 days3 x daily250 mgFamciclovir oral
7-10 days3 x daily5-10 mg/kgAcyclovir intravenous
7 days5 x daily800 mgAcyclovir oral
7 days3 x daily1000 mgValaciclovir oral
Gross et al., J. Clin. Virol., in press (2003)
![Page 45: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/45.jpg)
Brivudin compared to acyclovirIncidence of postherpetic pain
1.61 (1.15 – 2.25)Odds ratio (95% Cl)
0.006p value for difference
130 (43.5)101 (32.7)Patients with postherpetic pain n(%)
Acyclovir(n = 299)
Brivudin(n = 309)
Survey patients (n = 608)
A randomized, double-blind post-study survey on the effect of brivudinin the prevention of postherpetic pain in comparison with acyclovir
Prof. Dr. S.W. Wassilew
![Page 46: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/46.jpg)
Brivudin compared to famciclovir
0.0102p value for non-inferiority
1.23 (0.92 – 1.65)Odds ratio (95% Cl)
90 (9.2)109 (11.1)Patients with postherpetic pain n(%)
Famciclovir(n = 974)
Brivudin(n = 980)
ITT (n = 1954)
Prevalence of postherpetic pain
Brivudin compared to famciclovir in the prevention of postherpeticneuralgia: a prospective randomized, double-blind multicenter trial
Prof. Dr. S.W. Wassilew
![Page 47: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/47.jpg)
Brivudin compared to famciclovir
0.049p value for non-inferiority1.05 (0.76 – 1.45)Risk ratio (95% Cl)
72.9 ± 63.754.0
69.3 ± 62.847.0
Duration of postherpetic pain Mean ± SD Median
Famciclovir(n = 90)
Brivudin(n = 109)
ITT (n = 199)
Duration of postherpetic pain
Brivudin compared to famciclovir in the prevention of postherpeticneuralgia: a prospective randomized, double-blind multicenter trial
Prof. Dr. S.W. Wassilew
![Page 48: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/48.jpg)
Prof. Dr. S.W. Wassilew
Brivudin compared to famciclovirDuration of ZAP (Zoster-Associated Pain), n = 1712
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 30 60 90 120 150 180 210 240 270
D uration of ZA P [days, after start of treatm ent]
B rivud in
F am ciclo vir
Prob
abilit
y
![Page 49: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/49.jpg)
Nucleoside AnaloguesNon-nucleoside Analogues
![Page 50: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/50.jpg)
4-Hydroxyquinoline-3-carboxamides(4-HQC)
PNU-181465
inhibit replication of HSV-1, VZV and HCMV, through inhibitory effect on HSV-1, VZV and HCMV DNA polymerase
Oien et al., Antimicrob. Agents Chemother. 46: 724-730 (2002)
N
HO
OH
NH
O
Cl
![Page 51: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/51.jpg)
BILS 179 BS
inhibits replication of HSV (and other herpesviruses ?) through inhibitoryeffect on helicase/primase (UL5, UL8 and UL52 gene products)
Crutz et al., Nature Medicine 8: 386-391 (2002)
N
N
O
HN
O
H3C N
SNH2
![Page 52: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/52.jpg)
N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide inhibits replication of HSV (and other herpesviruses ?) through inhibitory effect on helicase /primase (UL5, UL8 and UL52 gene products)
BAY 57-1293
N O
N
CH3
N
SS NH2
O
O
CH3
Kleymann et al., Nature Medicine 8: 392-398 (2002)
![Page 53: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/53.jpg)
BAY 57-1293 in the rat lethal challenge model
Lewis rats were inoculated with HSV-1walki intranasally and were treated via oral gavage t.i.d. from day 0 to day 4 post infection. Five animals for eachgroup were used.
Betz et al., Antimicrob. Agents Chemother. 46: 1766-1772 (2002)
_####_ Placebo_≤≤≤≤_ Valaciclovir 45 mg/kg_X_ Valaciclovir 135 mg/kg_ππππ_ BAY 57-1293 0.5 mg/kg_′′′′_ BAY 57-1293 2 mg/kg
![Page 54: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/54.jpg)
BAY 57-1293 in the murine lethal challenge model
Mice were infected intranasally with HSV-2 MS and were treated via oral gavage once-daily from day 0 to day 4 post infection. Ten animals for each group were used.
Betz et al., Antimicrob. Agents Chemother. 46: 1766-1772 (2002)
12
![Page 55: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/55.jpg)
1,4-Dihydroxynaphthalene 1,4-Naphthoquinone
inhibit HSV-1 and HCMV proteases, could be considered as scaffold for development of non-peptidic anti-herpesvirus agents
Matsumoto et al., Biol. Pharm. Bull. 24: 236-241 (2001)
OH
OH
O
O
![Page 56: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/56.jpg)
CMV423
2-Chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide
inhibits HCMV replication, acts at an early stage (coinciding with IE antigensynthesis) of the HCMV replication cycle
Snoeck et al., Antiviral Res. 55: 413-424 (2002)
N
N
Cl
ONH2
![Page 57: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/57.jpg)
Pyrrolopyrimidines
828 951 1028
inhibit HCMV replication, target a viral protein that is expressed early in the HCMV replication cycle
Jacobson et al., Antimicrob. Agents Chemother. 43: 1888-1894 (1999)
N
N N
SNH2NH2
OH3CO
N
N N
SNH2NH2
H3CO
N
N N
CNNH2
H3C
NH2
![Page 58: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/58.jpg)
Naphthyridine and dihydroisoquinoline derivatives
7,8-Dihydroisoquinoline-6-carboxyl-[2-(1-indol-3-yl)ethyl]amide
inhibits HCMV (and HSV) replication, affects early (post-adsorption) event(s) of HCMV replication cycle
Bedard et al., Antimicrob. Agents Chemother. 44, 929-937 (2000)
NHN
O NH
![Page 59: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/59.jpg)
BAY 38-4766
inhibits HCMV replication, targets HCMV DNA maturation via UL89 and UL56 gene products, inhibits cleavage of high-molecular-weight DNA concatemers and packaging of monomeric genomes into procapsids
Buerger et al., J. Virol. 75: 9077-9086 (2001)
3-Hydroxy-2,2-dimethyl-N-[4({[5-dimethylamino)-1-naphthyl]sulfonyl}amino)-phenyl]propanamide
NH3C CH3
SNH
O
HN
O
O
OH
CH3
CH3
![Page 60: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/60.jpg)
BDCRB
1-(ββββ-D-Ribofuranosyl)-2-bromo-5,6-dichlorobenzimidazole
inhibits HCMV replication, targets HCMV DNA maturation via UL89 and UL59 gene products which are responsible for cleavage of high-molecular-weight DNA concatemers and packaging of monomeric genomes into procapsids
Biron et al., Antimicrob. Agents Chemother. 46: 2365-2372 (2002)
O
HO
HO
OH
N
NBr
Cl
Cl
![Page 61: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/61.jpg)
1263W94Maribavir
1-(ββββ-L-Ribofuranosyl)-2-isopropylamino-5,6-dichlorobenzimidazole
inhibits HCMV replication, through interaction with the UL97 gene product(which is required for egress of viral nucleocapsids from the nucleus)
Biron et al., Antimicrob. Agents Chemother. 46: 2365-2372 (2002)[Krosky et al., J. Virol. 77: 905-914 (2003)]
O
HO OH
OH
N
NNH
Cl
Cl
CH3
CH3
![Page 62: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/62.jpg)
Indolocarbazoles
Gö 6976inhibit HCMV replication, target UL97 gene product (which is required for egress of viral nucleocapsids from the nucleus)
Zimmermann et al., Antiviral Res. 48: 49-60 (2000)[Krosky et al., J. Virol. 77: 905-914 (2003)]
N N
HNO
CN
CH3
![Page 63: Download presentation as](https://reader031.fdocuments.net/reader031/viewer/2022021009/6203ae3dda24ad121e4c38c7/html5/thumbnails/63.jpg)
CONCLUSIONMarketed antiviral drugs for treatment of HSV, VZV and CMVinfections:
HSV VZV CMV
AcyclovirValaciclovirFamciclovirBrivudin
GanciclovirValganciclovirFoscarnetCidofovirFomivirsen