Transcript Mechanism of Action

Chapter 21
Antiviral Agents
抗病毒药物
20-400 nm
The A(H1N1) Virus
甲型H1N1病毒
2009，April
Influenza A virus subtype H1N1, also known as A(H1N1), is a subtype of
influenzavirus A and the most common cause of influenza (flu) in humans.
Some strains of H1N1 are endemic in humans, including the strain(s) responsible
for the 1918 flu pandemic which killed 50–100 million people worldwide. H1N1
strains caused roughly half of all flu infections in 2006.
Virus Structure and Classification
Viruses consist of a nucleic acid core that
contains either DNA or RNA
The protein coat called an envelope, which is
composed of glycoproteins, important virus antigens
The glycoprotein become attached to the receptor
Sites (polypeptide) on the host cell
HIV virus picture
The penetration, uncoating, and release of the virions（病毒体） in
the host cell depend on the structural coat proteins
Viral Replication and Transformation
病毒的复制和转化
1 Attachment
2 Penetration
3 Uncoating and transfer of viral DNA to
nucleus
4 Early transcription into viral mRNA
5 Early translation of viral mRNA into
enzymes for viral DNA synthesis
6 Synthesis of viral DNA and late
transcription of viral mRNA
7 Late translation of mRNA into viral
structural proteins
8 Assembly of virus particles in nucleus
9 Budding from nucleus and release of
virions
Viral Drug Therapy
Agents inhibiting virus attachment, penetration and early viral replication
抑制病毒复制早期的药物
Amantadine
金刚烷胺
NH2
HCl
Tricyclic primary amine
三环伯胺
Mechanism of Action: Amantadine inhibits penetration of RNA virus particles
into the host cell; the early stages of viral replication
金刚烷胺抑制RNA病毒穿透宿主细胞
Clinical Application: Amantadine is effective clinically in preventing and treating
all A strains of influenza, particularly A2 strains of Asian influenza virus
Amantadine （金刚烷胺）
Pharmacokinetics（药代动力学）:
 Half-life is 15-20 hour
 90% is excreted unchanged by the kidney
 There are no reports of metabolic products
Side Effects（副作用）:
 Generally, the drug has low toxicity at therapeutic level
 Severe central nervous system (CNS) symptoms（中枢神经系统）
H2N
CH3
Rimantadine （金刚乙胺）
HCl
Mechanism of Action:
 More effective than amantadine hydrochloride against influenza A virus
 Interfere with virus uncoating by inhibiting release of specific proteins
 It may act by inhibiting RT or the synthesis of virus-specific proteins
Pharmacokinetics:
 The half-life of rimantadine in adults ranges from 24-36 hours
 Over 90% of rimantadine doses were absorbed in 3-6 hours
Interferon （干扰素）
 Interferon are polypeptide hormones, or glycoproteins, MW 20-160kD
 It is produced by the cells immune system in response to foreign challenge,
like virus, parasites or tumor cell
Types of Interferon: according to the type of receptor through which they signal
Type α,β,γ
Interferon Induction: “inducers”
Various small molecules and large polymers
O
H3C
N
O
O
H3C
N
CH3
CH3
Tilorone， 替洛隆
Neuraminidase Inhibitors （NA，神经氨酸酶抑制剂）
NA is found in both influenza A and B viruses
NA is a glycoprotein
The viruses are bound to the NA through the sialic acid （唾液酸）
and the NA cleaves the sialic acid moiety
HO
COOH
HO
H3C
HO
HO
H
N
O
HO
O
O
OH
HO
sugar
Neuraminidase
H3C
H
N
HO
COOH
O
H3C
HO
O
OH
H
N
O
HO
O
Transition state
HO
H3C
COOH
OH
HO
H
N
O
OH
+ Glycoprotein
HO
O
Sialic acid
Sialic acid hydrolysis catalyzed by neuraminidase
神经氨酸酶催化的唾液酸水解
COOH
Structural derivatives of sialic acid as neuraminidase inhibitors
唾液酸衍生物作为神经氨酸酶抑制剂
HO
COOH
HO
H
N
H3C
HO
OH
O
H
O
O
COOH
HN
H3C
H
HN
COOC2H5
H3C
O
HN
COOH
HN
DANA
Sialic acid
HO
O
O HO
O
OH
H
H3C
HO
HO
OH
HO
NH2
Aanamivir
OH N
2
Oseltamivir phosphate
6-C ring, prodrug
3 Agents Interfering with Viral Nucleic Acid Replication
干扰病毒核酸复制的药物
Mechanism of Action:
Binding to DNA or RNA polymerase, competitive binding Vs native substrate
1) Nucleoside：Pyrimidine 核苷类：嘧啶
O
I
HN
HO
O
O
N
O
碘苷
OH
Idoxuridine
CH3
HN
HO
O
N
O
OH
脱氧胸腺嘧啶苷
Thymidine
 Idoxuridine is a nucleoside containing a halogenated pyrimidine and is an
analogue of thymidine
 Acts against DNA viruses
Idoxuridine Mechanism of Action: 链终止
 Idoxuridine is first phosphorylated by the host cell to an active triphosphate form
 The phosphorylated drug is incorporated during viral nucleic acid synthesis by
a false pairing system that replaces thymidine, results in chain termination.
O
I
HN
HO
O
N
O
OH
Idoxuridine
O
O
O
thymidine kinase HO P O
OH
I
HN
O
O
OH
N
O
O
O
HO P O P O P O
OH OH OH
I
HN
O
O
OH
triphosphate form
Active form
N
Other Nucleoside Pyrimidine Analogue Inhibitors
O
F
HN
HO
O
N
O
HO
O
OH
Br
HN
N
O
OH
Fluorodeoxyuridine Bromodeoxyuridine
氟苷
溴苷
Same mechanism
Increased potency
NH2
O
O
CF3
HN
HO
O
N
O
OH
Trifluorothymidine
TFT, F3T
三氟胸苷
HO
N
O
HO
O
N
OH
Cytarabine
阿糖胞苷
Pyrimidine analog
Same mechanism
Anticancer
2 Purine Analogs （嘌呤核苷类）
NH2
N
Vidarabine
N
HO
O
HO
阿糖腺苷
N
N
Streptomyces antibioticus
链霉菌
OH
Mechanism of Action：Cellular enzymes convert Vidarabine to mono, di-,
and triphosphate derivatives that interfere with viral nucleic acid replication
Metabolism of Vidarabine
阿糖腺苷的代谢
N
Adenine deaminase
腺嘌呤脱氨酶
HO
O
NH2
N
HO
O
OH
Vidarabine
N
N
N
Deamination
HO
N
HO
O
NH
N
OH
Arabinofuranosylhypoxanthine
Acyclovir（阿昔洛韦）and Valaciclovir （伐昔洛韦）
O
N
N
HO
O
N
NH
N
CH3 O
NH2
O
H3C
Acyclovir
N
O
NH
N
NH2
O
NH2
Valacyclovir
Acyclovir is a synthetic analogue of deoxyguanosine（脱氧鸟苷）,
The carbohydrate moiety is acyclic
The active form is the triphosphate form
Mechanism of Action
 Acyclovir is converted to monophosphate, di- and tri-phosphate form
This phosphorylation reaction occurs faster by cells infected by virus than by normal cells
 Viral DNA polymerase （DNA 聚合酶） is competitively inhibited by
triphosphate form at lower concentrations than is cellular DNA polymerase
The triphosphate is incorporated into the viral DNA chain during DNA synthesis
Lacks of the 3’OH of a cyclic sugar, terminates further elongation of the DNA chain
 Preferential uptake of acyclovir by virus –infected cell results in a higher
concentration of acyclovir triphosphate, which leads to a high ratio of
therapeutic value to toxicity ratio of infected cells to normal cells
Mechanism of Action
O
N
N
HO
O
N
NH
N
NH2
O
thymidine kinase
胸苷激酶
Acyclovir
O
HO P O
OH
N
O
NH
N
guanosine
NH2 monophosphate kinase
鸟嘌呤核苷单磷酸激酶
O
O
N
O
O
HO P O P O
OH OH
N
O
N
NH
N
guanosine
NH2 diphosphate kinase
O
O
O
HO P O P O P O
OH OH OH
N
O
NH
N
NH2
Synthesis of Acyclovir
O
O
N
N
H
H2N
O
N Ac
Ac2O
(AcO)2ZnAc
H2N
N
O
O
S OH
O
H3C
鸟嘌呤
O
N
O
H3C
O
N
H
N
N
O
O
CH3
O
hydrolysis
40% CH3NH2
H2N
N
O
OH
Drawback of Acyclovir
O
N
N
HO
NH
N
NH2
O
Acyclovir
阿昔洛韦
Poor water solubility
Poor absorption
Drug resistance
N
oxidation
N
HO
N
N
NH2
O
desciclovir
地昔洛韦
18 times enhanced solubility
Good absorption
Decreased side effect
Prodrug, be oxidized to acyclovir in vivo
More Acyclovir Related Drugs O
N
NH2
O
N
NH
N
O
O
N
NH
N
NH2
N
NH2
O
HO
O
Valaciclovir 伐昔洛韦
HO
Ganciclovir 更昔洛韦
O
Higher potency
Toxicity，活性高，毒性大
Good GI absortption
肠胃吸收好
O
N
N
N
NH
N
NH2
N
O
N
N
NH2
O
HO
HO
Penciclovir 喷昔洛韦
Stable triphosphate form
Longer half-life
三磷酸酯稳定，半衰期长
O
Famciclovir 泛昔洛韦
O
Better bioavailability
生物利用度较好
3 Non-nucleoside antiviral drugs
非核苷类抗病毒药物
O
H2N
N
N
Ribavirin 利巴韦林
HO
N
O
HO
OH
A guanosine analogue (X-ray crystallography)
Broad-spectrum antiviral activity against both DNA and RNA viruses
Mechanism of Action:
It is phosphorylated to the triphosphate， resulting in inhibition of viral
specific RNA polymerase, messenger RNA, and nucleic acid synthesis
Synthesis of Ribavirin
O
O
O
N
OCH3
N
O
N N
H
triazole
OAc
AcO
AcO
N
H+
O
+
AcO
OAc
glycoside
N
O
AcO
OAc
NH2
N
HO
N
CH3OH/NH3
O
HO
OH
N
Anti-HIV Agents
抗艾滋病药物
HIV virus
Virus life cycle
Anti-HIV targets
1 Reverstranscriptase（逆
转录酶） RNA-dependent DNA
polymerase, is a DNA Polymerase
enzyme that transcribes singlestranded RNA into doublestranded DNA
3D picture of reverstranscriptase
Reverse transcriptase was discovered by Howard Temin at the
University of Wisconsin-Madison, and independently by David Baltimore
in 1970 at MIT.
The two shared the 1975 Nobel Prize in Physiology or Medicine
with Renato Dulbecco for their discovery.
2 Protease
蛋白酶
HIV-1 protease (HIV PR) is an aspartic protease, HIV PR cleaves newly
synthesized polyproteins at the appropriate places to create the mature
protein components of an infectious HIV virion.
3 Intergrase
整合酶
Integrase is an enzyme produced by a retrovirus (逆转录病毒，including HIV)
that enables its genetic material to be integrated into the DNA of the infected cell.
It is also produced by viruses containing double stranded DNAs for the same
purpose. It is a key component in the pre-integration complex
Reverse Transcriptase Inhibitor: nucleoside, non-nucleoside
逆转录酶（RT）抑制剂：核苷类与非核苷类
Nucleoside Reverse Transcriptase Inhibitor: AZT
O
3’-azido-3’-deoxythymidine
Zidovudine
齐夫多定
CH3
HN
HO
O
N
O
N3
AZT
Mechanism of Action: the N3 group at 3’position, instead of OH, inhibits
the 3’,5’diphosphate ester bond formation, chain terminator
Synthesis of AZT
O
CH3
HN
F
F
HO
O
O
O
N
O
F
N
Cl
OH
CH3
N
HO
O
O
N
CH3
HN
LiN3
HO
O
N
O
NH4Cl, DMF
N3
Deoxythymidine，
脱氧胸腺嘧啶核苷
Mechanism of Action:
AZT is activated in vivo by thymidine kinase,
Thymidylate kinase and nucleoside diphosphate kinase to AZTTP
Other NT Inhibitors
NH2
N
HO
O
CH3
HN
N
O
NH2
O
HO
O
N
O
N
O
HO
N
N
O
O
HO
N
NH
N
O
S
Zalcitabine, ddC
扎西他滨
Pyrimidine analog
High bioavailability
Side effects:
stomatitis, rash,
fever, malaise,
arthritis, et al
Stavudine, d4 T
司他夫定
Lamivudine, 3TC
Didanosine, ddI
拉米夫定
去羟肌苷
Pyrimidine analogue Rapidly absorbed Purine dideoxynucleoside
Through GI tract
Given in advanced HIV infection
High bioavailability
Combination with
Low toxicity
DDI, ddC or d4T
Side effect:
Pain, tingling, numbness
in hands and feet
Side effect:
Painful peripheral
neuropathy and pancreatitis
HN
Abacavir, ABC
阿巴卡韦
N
HO
NH2
N
University of Minnesota
College of pharmacy
Dr. Robert Vince
Dr. Mei Hua
二 Nonnucleoside RT Inhibitors (NNRTI)
非核苷类
HC
O
3
HN
From structure-based drug design methodology
Effective against AZT-resistant HIV strains
Combination with ZDV and ddI
Side effect: liver dysfunction and skin rashes
N
N
N
Nevirapine 奈韦拉平
Mechanism of Action:
Dipyridodiazepinone derivative ,
Binds directly to RT, blocks RNA- and DNA-dependent polymerase
activity by causing a disruption of the enzyme’s catalytic site
三 HIV Protease Inhibitors
蛋白水解酶抑制剂
HIV protease exists as a dimer
Each monomer contains one aspartic
residues at the active site
Drugs are designed as transition-state
mimetics to align at the active site
1) Peptide
2) Peptide mimetics
3) nonpeptide
Protease Inhibitors
Ritonavir, 利托那韦
沙奎那韦
Indinavir, 茚地那韦
Nelfinavir, 萘非那韦
nonpeptide
Integrase inhibitors
MK-0518, Merck, approved in Sept. 2007
2nd, GS-9139, approved in 2008, Gilead
The HAART （鸡尾酒疗法）：
highly active antiretroviral therapy
David Ho （何大一）
Taiwanese American
Time magazine, Man of the Year, 1996
Synergistic effect
1 + 1 > 2
Summary:
DNA, RNA virus
Virus replication cycle
Inhibit the earlier stage:
 amantadine HCl, rimantadine HCl;
 Interferon, α,β,γ; Inducer: tilorone
 The Neuraminidase, NA inhibitor, transition state inhibitor
Agents interfere the nucleoside replication
 Nucleoside, analogs of purine and pyrimidine
 Nonnucleoside: structure-based drug design
Mechanism of Action: activated in vivo by kinase to triphosphate form
Typical StructuresＩ
O
HN
NH2
HO
HCl
O
NH2
I
N
N
HO
O
Amantadine
N
HO
O
OH
OH
Idoxuridine
O
N
N
HO
NH
N
O
CH3 O
NH2
H3C
N
O
N
Vidarabine
O
O
N
N
H2N
N
NH
N
N
NH2 HO
N
O
O
NH2
Acyclovir
Valacyclovir
HO
OH
Ribavirin
Anti HIV Agents, NNRT inhibitors
NH2
O
CH3
HN
O
HO
N
N
O
HO
AZT
O
HO
N
N
O
N
O
Stavudine, d4 T
HO
N
HN
NH
N
N
O
S
Lamivudine, 3TC
O
O
N
HO
N
Zalcitabine, ddC
NH2
CH3
HN
O
O
N3
O
Didanosine, ddI
HO
NH2
N
Abacavir
Protease Inhibitors
Ritonavir, 利托那韦
沙奎那韦
Indinavir, 茚地那韦
Nelfinavir, 萘非那韦
nonpeptide
Integrase inhibitors
MK-0518, Merck, approved in Sept. 2007
Generic name: Raltegravir
2nd, GS-9139, approved in 2008, Gilead