Transcript Respiratory virus inhibitors - Pharmacie - UCL

TREATMENT OF VIRAL RESPIRATORY
INFECTIONS
Erik DE CLERCQ
Rega Institute for Medical Research, K.U.Leuven
B-3000 Leuven, Belgium
RESPIRATORY TRACT VIRUS INFECTIONS
ADENOVIRIDAE
: Adenoviruses
HERPESVIRIDAE
: Cytomegalovirus, Varicella-zoster virus
PICORNAVIRIDAE
: Enteroviruses (Coxsackie B, ECHO)
Rhinoviruses
CORONAVIRIDAE
: Coronaviruses
ORTHOMYXOVIRIDAE : Influenza (A, B, C) viruses
PARAMYXOVIRIDAE
: Parainfluenza viruses
Respiratory syncytial virus
“SARS (Severe Acute Respiratory
Disease) virus”
RESPIRATORY TRACT VIRAL DISEASES
Adenoviruses: Adenoiditis, Pharyngitis, Bronchopneumonitis
Cytomegalovirus: Interstitial pneumonitis
Varicella-zoster virus: Pneumonitis
Enteroviruses (Coxsackie B, ECHO): URTI (Upper Respiratory Tract
Infections)
Rhinoviruses: Common cold
Coronaviruses: Common cold
Influenza viruses: Influenza (upper and lower respiratory tract infections)
Parainfluenza viruses: Parainfluenza (laryngitis, tracheitis)
Respiratory syncytial virus: Bronchopneumonitis
INFLUENZA VIRUS
Influenza virus
Electron micrographs of purified influenza virions. Hemagglutinin (HA ) and
neuraminidase (NA) can be seen on the envelope of viral particles.
Ribonucleoproteins (RNPs) are located inside the virions.
http://www.virology.net/Big_Virology/BVRNAortho.html
Influenza
Layne et al., Science 293: 1729 (2001)
NA (neuraminidase)
Lipid bilayer
M1 (membrane protein)
RNPs (RNA, NP)
M2 (ion channel)
Transcriptase complex
(PB1, PB2 and PA)
HA (hemagglutinin)
Simplified representation of the influenza virion showing the neuraminidase
(NA) glycoprotein, the hemagglutinin (HA) glycoprotein and the matrix M2
protein
M2
McClellan and Perry, Drugs 61: 263-283 (2001)
Distribution of influenza A hemagglutinin (H) subtypes in nature
Figure adapted from Murphy & Webster. Orthomyxoviruses.
http://www.brown.edu/Courses/Bio_160/Projects1999/flu/mechanism.html
Distribution of influenza A hemagglutinins in nature
http://www.brown.edu/Courses/Bio_160/Projects1999/flu/mechanism.html
Distribution of influenza A neuraminidases in nature
http://www.brown.edu/Courses/Bio_160/Projects1999/flu/mechanism.html
Amantadine/rimantadine:
mechanism of action limited to influenza A viruses
H
NH2.HCl
H
H
Amantadine
Symmetrel®
H
NH2.HCl
H
CH3
H
Rimantadine
Flumadine®
The tetrameric M2 helix bundle
Sansom & Kerr, Protein Eng. 6: 65-74 (1993)
Neuraminidase (NA):
Cleaves sialic acid from cell-surface glycoprotein
Glycoproteins and neuraminidase
Sialic acid
Sialic acid
2,3
Galactose

Galactose
1,4
N-acetyl-glucosamine
N-acetyl-glucosamine
Core sugars
Core sugars
protein
protein
Influenza virus neuraminidase
Functions:
• removes terminal sialic acid residues
• promotes release of virus particles from the
cells
• destroys cellular receptors recognized by
hemagglutinin
• prevents virus aggregation at the cell surface
• prevents viral inactivation by respiratory mucus
NEURAMINIDASE INHIBITORS
GG167
4-Guanidino-Neu5Ac2en
Zanamivir
Relenza®
GS4104, Ro64-0796
Ethyl ester of GS4071
Oseltamivir
Tamiflu®
HO
OH
H
HO
H
N
H3C
O
O
OH
OH
O HO
Sialic acid
N-Acetylneuraminic acid (NANA)
HO
HO
OH
OH
HO
O
H
OH
O
O
H
O
H
N
H3C
HO
HO
R
Sialyl -glycoside
R = glycoprotein
influenza
neuraminidase
O
O
O
H
N
H3C
+
OH
O HO
R
Transition state
Abdel-Magid et al., Curr. Opin. Drug Discov. Dev. 4: 776-791 (2001)
HO
HO
OH
OH
HO
HO
H
O
H
N
H3C

H2O
O
H
N
H3C


O
O
HO
OH
HO
R-O-
Transition state
O
H
R-OH
Sialic acid
Abdel-Magid et al., Curr. Opin. Drug Discov. Dev. 4: 776-791 (2001)
HO
OH
HO
H
O
H
N
H3C


O
HO
DANA
Abdel-Magid et al., Curr. Opin. Drug Discov. Dev. 4: 776-791 (2001)
HO
OH
HO
H
O
H
N
F


F
F
O
HO
FANA
Abdel-Magid et al., Curr. Opin. Drug Discov. Dev. 4: 776-791 (2001)
HO
OH
HO
H
O
H
N
H3C


O
HN
NH
H2N
Zanamivir
Relenza®
HO
O
P
HO
H3C
O
H3C

H
N
H3C
O
O
NH2
CH3
Oseltamivir phosphate
Tamiflu®
OH
Oseltamivir = GS4104 = oral prodrug
(ethyl ester) form of GS4071
H3 C
O
H3 C
O
H
N
C
H3 C
OH
O
NH2
GS4071
GS4071 bound to influenza neuraminidase
Kim et al., J. Am. Chem. Soc. 119: 681-690 (1997)
GS4071 bound to influenza neuraminidase
Zanamivir (Relenza®)
• active against both influenza A and B
• IC50 : 0.21-2.6 ng/ml for influenza neuraminidase
• efficacy demonstrated in mouse and ferret models for
influenza (upon topical administration)
• has to be administered by inhalation : 10 mg bid
• therapeutically effective (5 days) : significant reduction in
duration of illness
• prophylactically effective (4 weeks) : significant reduction in
number of ill subjects
• well tolerated : clinical adverse events not different from
placebo
• no evidence for emergence of drug-resistant virus
Oseltamivir (Tamiflu®)
• active against both influenza A and B
• IC50 : < 1 ng/ml for influenza neuraminidase
• efficacy demonstrated in mouse and ferret models for
influenza (upon oral administration)
• can be administered orally : 75 or 150 mg bid
• therapeutically effective (5 days) : significant reduction in
duration of illness
• prophylactically effective (6 weeks) : significant reduction in
number of ill subjects
• well tolerated : clinical adverse events not different from
placebo
• no evidence for emergence of drug-resistant virus
RESISTANCE MUTATIONS TO NEURAMINIDASE
INHIBITORS
Neuraminidase
119 Glu  Gly:
• specific for zanamivir;
• Glu 119 interacts with guanidinium group of zanamivir
292 Arg  Lys:
• found for zanamivir; cross-resistance to oseltamivir
• Arg 292 interacts with carboxylic acid group of
zanamivir and oseltamivir
Hemagglutinin
Some mutations (i.e. 198 Thr  Ile) diminish affinity of
hemagglutinin for its receptor
McKimm-Breschkin, Antiviral Res. 47: 1-17 (2000)
Benefits offered by neuraminidase inhibitors
Therapeutically:
• Reduction in illness duration by 1-2 days
• Reduction in risk-virus transmission to household or
healthcare contacts
• Reduction in complications (sinusitis, bronchitis)
• Reduction in use of antibiotics
Prophylactically:
• Seasonal prevention of infection
H2N
NH
O
HN
OH
H
N
H
OH
H3C
O
CH3
CH3
RWJ-270201
Smee et al., Antimicrob. Agents Chemother. 45: 743-748 (2001)
Sidwell et al., Antimicrob. Agents Chemother. 45: 749-757 (2001)
H3C
O
CH3
N
CH3
F F
N
F
O
HO
NH2
O
A-192558
Wang et al., J. Med. Chem. 44: 1192-1201 (2001)
CH3
H
N
H3C
O
H3C
H
OH
N
H H
O
O
CH3
A-315675
DeGoey et al., J. Org. Chem. 67: 5445-5453 (2002)
Hanessian et al., J. Am. Chem. Soc. 124: 4716-4721 (2002)
N
F
OH
NH2
N
O
T-705
T-705 showed potent inhibitory activity against influenza A, B, and C viruses,
with 50% effective inhibitory concentrations of 0.013 to 0.48 µg/ml, while it showed
no cytotoxicity at concentrations up to 1,000 µg/ml. T-705 was also active against
a neuraminidase inhibitor-resistant virus and amantadine-resistant viruses.
Furuta et al., Antimicrob. Agents Chemother. 46: 977-981 (2002)
HUMAN RHINOVIRUS (HRV)
HRV 14
Human rhinovirus type 14
Antirhinoviral targets for therapy
Agents can (a) prevent viral attachment to host-cell receptors (ICAM-1 and the low density
lipoprotein receptor), (b) inhibit viral uncoating or (c) inhibit viral protein synthesis by
blocking 3C viral protease.
McKinlay, Curr. Opin. Pharmacol. 1: 477-481 (2001)
O
C
H3C
O
O
C2H5
(CH2)6 CH
C
C2H5
O
Phenoxyalkyldiketone
Arildone
WIN38020
De Clercq, In: Antiviral Agents and Human Viral Diseases.
Galasso, Whitley & Merigan, eds. Lippincott-Raven Publishers, pp 1-44 (1997)
N
O
O
(CH2)7
O
N
H3C
Isoxazole
Disoxaril
WIN 51711
De Clercq, In: Antiviral Agents and Human Viral Diseases.
Galasso, Whitley & Merigan, eds. Lippincott-Raven Publishers, pp 1-44 (1997)
CH3
N
H3C
O
N
N
N
Pyridazinamine
R61837
De Clercq, In: Antiviral Agents and Human Viral Diseases.
Galasso, Whitley & Merigan, eds. Lippincott-Raven Publishers, pp 1-44 (1997)
N
H3C
O
N
N
(CH2)2 O
C
O
C2H5
Phenoxypyridazinamine
Pirodavir
R77975
De Clercq, In: Antiviral Agents and Human Viral Diseases.
Galasso, Whitley & Merigan, eds. Lippincott-Raven Publishers, pp 1-44 (1997)
Interaction of WIN 52035 with VP1 of human rhinovirus (HRV-14)
Andries, In: Antiviral Chemotherapy. Jeffries & De Clercq, eds. John Wiley & Sons, Chichester, pp 287-319 (1995)
Interaction of R61837 with VP1 of human rhinovirus (HRV-14)
Andries, In: Antiviral Chemotherapy. Jeffries & De Clercq, eds. John Wiley & Sons, Chichester, pp 287-319 (1995)
CF3
N
O
N
O
N
O
Pleconaril (VP-63843)
Romero, Exp. Opin. Invest. Drugs 10: 369-379 (2001)
BTA188
H3C
N
N
N
N
O
CH2 CH3
O
BTA showed potent in vitro activity against 87 of 100 rhinovirus serotypes
with a median EC50 of 10 ng/ml, superior to pleconaril.
BTA188 is targeted at the hydrophobic pocket in the core of VP1.
Hayden et al., Antiviral Res. 50: A127 (2001)
Benzothiazole
H3C
N
N
S
S
S
N
Benzothiazole targeted at hydrophobic pocket in the core of VP1.
EC50 against HRV-14 in cell culture: 0.8 µM.
Tsang et al., Chem. Biol. 8: 33-45 (2001)
Ruprintrivir
O
NH
O
O
N
H
H3 C
O
N
N
H
O
O
CH2
O
CH3
F
Inhibitor of human rhinovirus C3 protease, currently undergoing clinical
evaluation for the prevention and treatment of the common cold.
Hsyu et al., Antimicrob. Agents Chemother. 46: 392-397 (2002)
Pyridone
O
NH
O
O
N
N
H
H3 C
O
N
N
H
O
CH3
O
CH
O
F
CH3
F
Human rhinovirus (HRV) 3C protease inhibitor showed an average EC50
of 45 nM across 15 serotypes of HRV.
Dragovich et al., J. Med. Chem. 45: 1607-1623 (2002)
RESPIRATORY SYNCYTIAL VIRUS (RSV)
Respiratory Syncytial Virus (RSV) and Parainfluenza Virus (PIV)
Hall, N. Engl. J. Med. 344: 1917-1928 (2001)
Characteristics of the proteins of respiratory syncytial virus and
parainfluenza virus
Protein
Molecular mass
Respiratory
syncytial virus
Functions
Parainfluenza
virus
kilodaltons
Structural protein
Surface
Fusion (F)
68
60
Penetration; major protection antigen
Attachment (G)
90
—a
Viral attachment; major protective antigen
Hemagglutinin neuraminidase
(HN)
—a
69
Viral attachment and release; major protective antigen
4.8 – 30b
—a
Unknown
28
22b
40
—a
Mediates attachment of nucleocapsid to envelope
Small hydrophobic (SH [1A])
Matrix
Matrix (M)
Small envelope (M2)
Transcriptional regulation; unique to pneumoviruses
Nucleocapsid-associated
Nucleoprotein (N, NP)
44
58
Major RNA-binding nucleocapsid protein
Phosphoprotein (P)
37
60
Major phosphorylated protein; RNA-dependent RNA polymerase
activity
Large polymerase complex (L)
200
250
Large nucleocapsid-associated protein; major polymerase subunit;
RNA-dependent RNA polymerase activity
aNot
present in the virus.
are four glycosylated and nonglycosylated forms with molecular masses of 4.8, 7.5, 13 to 15, and 21 to 30 kd.
bThere
Hall, N. Engl. J. Med. 344: 1917-1928 (2001)
Number of cases or isolates
Epidemiologic pattern of infections with respiratory syncytial virus
in relation to the occurrence of bronchiolitis from 1993 through 1998
1993
1994
1995
1996
1997
1998
Hall, N. Engl. J. Med. 344: 1917-1928 (2001)
Proportion of samples taken from cases of influenza-like illness positive for
influenza or respiratory syncytial virus in 0-5-year-olds during 1996-1997
Zambon et al., Lancet 358: 1410-1416 (2001)
Proportion of samples taken from cases of influenza-like illness positive for
influenza or respiratory syncytial virus in 0-5-year-olds during 1996-1997
Zambon et al., Lancet 358: 1410-1416 (2001)
O
N
H2N
N
N
HO
O
HO
OH
Ribavirin
Virazole®
RFI-641
H2N
O
N
H2N
S
O
O
NH2
O
O
NH
N
HN
N
NaO3S
O
O
S
N
O
H2 N
O
NH2
S
O
N
HN
N
O
O
NH
N
SO3 Na
N
NH
N
HN
O
H2 N
O
O
S
N
NH2
O
NH2
RFI-641 inhibits RSV fusion mediated by F (Fusion) protein, but also interferes
with the attachment (G) protein
Nikitenko et al., Bioorg. Med. Chem. Lett. 11: 1041-1044 (2001)
Razinkov et al., Chem. Biol. 8: 645-659 (2001)
Morphology of CV-1 cells treated with RFI-641
(A) Noninfected, nontreated CV-1 cells; (B) RSV-infected, untreated
CV-1 cells; (C) RSV-infected, RFI-641 (> 8 h)-treated CV-1 cells
Huntley et al., Antimicrob. Agents Chemother. 46: 841-847 (2002)
Therapeutic efficacy of RFI-641 after intranasal administration
to RSV-infected African green monkeys
RFI-164 was administered intranasally, daily, starting 1 day after virus infection
Huntley et al., Antimicrob. Agents Chemother. 46: 841-847 (2002)
N
NH2
CH3
N
NH
N
N
CH3
HO
R-170591 interferes with RSV fusion
Andries et al., 40th ICAAC, Toronto, Canada, 17-20 September 2000, Abstract H-1160
Benzodithiin (RD3-0028)
S
S
RD3-0028 inhibits RSV replication by interfering with intracellular
processing of the RSV fusion protein, leading to loss of infectivity
Sudo et al., Microbiol. Immunol. 45: 531-537 (2001)
PARAMYXOVIRIDAE
• Paramyxovirinae
• Respirovirus/Paramyxovirus (Sendai virus,
Parainfluenza 1 and 3)
• Rubulavirus (Mumps virus, Parainfluenza 2, 4a and 4b)
• Morbillivirus (Measles virus)
• Megamyxovirus (Hendra and Nipah virus)
• Pneumovirinae
• Pneumovirus (Pneumovirus, Respiratory Syncytial Virus)
• Metapneumovirus (Human metapneumovirus)
PHYLOGENY OF THE PARAMYXOVIRINAE
HPIV-1
Sendai
HPIV-3
CDV
PDV
RPV
Measles
Genus
Respirovirus/
Paramyxovirus
Genus
Morbillivirus
PPRV
DMV
Tupaia
Tentative new genus
Megamyxovirus
Hendra
Nipah
HPIV-4b
HPIV-4a
Mumps
Genus Rubulavirus
SV5
HPIV-2
Mapuera
NDV
OUTBREAK-INSPIRED HUNT FOR VIRUSES
• Hendra virus
(1994, Megamyxovirus)
•Australian bat lyssavirus
(1996, Rhabdoviridae)
•Menangle virus
(1997, Rubulavirus)
•Tupaia virus
(1999, Paramyxovirus)
• Nipah virus
(1999, Megamyxovirus)
• Tioman virus
(2000, Rubulavirus)
•Dolphin, porpoise and cetacean morbillivirus
(1991, Morbillivirus)
•Salem virus
(2000, not yet classified)
DIFFERENCES BETWEEN
HENDRA & NIPAH VIRUS
Multiple host species
OTHER PARAMYXOVIRINAE
Host specific : human
Reservoir host :
• fruit bats (flying foxes) ?
Clinical hosts :
• horse, pig, man,...
Experimental hosts :
• guinea pig, cat
Not very contagious
No human-to-human spread,
but infection is very lethal
and
Highly contagious
Human-to-human spread,
droplet infection
CONCLUSION
APPROVED ANTIVIRAL DRUGS FOR THE TREATMENT OF
THE MAJOR RESPIRATORY TRACT VIRUS INFECTIONS
Adenoviruses
Picornaviruses
Entero
Rhino
Orthomyxoviruses
Influenza
: none
: none
: none
: Neuraminidase inhibitors:
zanamivir, oseltamivir
: Amantadine and rimantadine
(for influenza A only)
Paramyxoviruses
Parainfluenza
: none
Respiratory syncytial virus : Ribavirin
SARS virus
: none