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Chapter 21 Antiviral Agents抗病毒药物
20-400 nm
The A(H1N1) Virus甲型 H1N1 病毒
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.
2009 ， April
HIV virus picture
Virus Structure and Classification
Viruses consist of a nucleic acid core thatcontains either DNA or RNA
The protein coat called an envelope, which is composed of glycoproteins, important virus antigens
The glycoprotein become attached to the receptorSites (polypeptide) on the host cell
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 e
nzymes for viral DNA synthesis
6 Synthesis of viral DNA and late
transcription of viral mRNA
7 Late translation of mRNA into viral str
uctural 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
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
Tricyclic primary amine三环伯胺
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）
Rimantadine （金刚乙胺）
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
HCl
H2N CH3
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
OON
CH3
CH3N
H3C
H3C
O
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
Sialic acid hydrolysis catalyzed by neuraminidase神经氨酸酶催化的唾液酸水解
O
COOH
Osugar
HO
HN
H3C
O
HO
HO
OCOOH
HO
HN
OH
H3C
O
HO
HOO
COOH
HO
HN
OH
H3C
O
HO
HO
Transition state
Neuraminidase
O
COOH
OH
HO
HN
OH
H3C
O
HO
HO
Sialic acid
Glycoprotein+
Structural derivatives of sialic acid as neuraminidase inhibitors唾液酸衍生物作为神经氨酸酶抑制剂
O
COOH
OH
HO
HN
H3C
O
HO
HO
Sialic acid DANA
OCOOH
HO
HN
H
HO
H3C
OHHO
O
OCOOHHN
H
HO
H3C
OHHO
O
HN NH2
Aanamivir
COOC2H5
H2N
HN
HO
H3CO
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
Idoxuridine is a nucleoside containing a halogenated pyrimidine and is an analogue of thymidine Acts against DNA viruses
脱氧胸腺嘧啶苷碘苷
O
HO N
HN
OH
I
O
O
Idoxuridine
O
HO N
HN
OH
CH3
O
O
Thymidine
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.
Idoxuridine
O
HO N
HN
OH
I
O
O
O
O N
HN
OH
I
O
OPHO
O
OH O
O N
HN
OH
I
O
OPO
O
OH
P
O
O
OH
P
O
HO
OHthymidine kinase
triphosphate form
Active form
Other Nucleoside Pyrimidine Analogue Inhibitors
O
HO N
HN
OH
F
O
O
O
HO N
HN
OH
Br
O
O
O
HO N
HN
OH
CF3
O
OO
HO N
N
OH
NH2
OHO
Fluorodeoxyuridine Bromodeoxyuridine TrifluorothymidineTFT, F3T
Cytarabine
Same mechanismIncreased potency
Pyrimidine analogSame mechanismAnticancer
氟苷 溴苷 三氟胸苷 阿糖胞苷
2 Purine Analogs （嘌呤核苷类）N
NN
N
NH2
O
OH
HOHOVidarabine阿糖腺苷
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
NN
N
NH2
O
OH
HOHO
NH
NN
N
O
O
OH
HOHODeamination
Vidarabine Arabinofuranosylhypoxanthine
Adenine deaminase腺嘌呤脱氨酶
Streptomyces antibioticus链霉菌
Acyclovir （阿昔洛韦） and Valaciclovir （伐昔洛韦）
Acyclovir is a synthetic analogue of deoxyguanosine （脱氧鸟苷） ,
The carbohydrate moiety is acyclic
The active form is the triphosphate form
NH
NN
N
O
OHONH2
NH
NN
N
O
OONH2
O
NH2
H3C
CH3
Acyclovir Valacyclovir
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 synthesisLacks 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
NH
NN
N
O
OHONH2
Acyclovir
NH
NN
N
O
OONH2
PHO
O
OH
NH
NN
N
O
OONH2
PO
O
OH
PHO
O
OH
NH
NN
N
O
OONH2
PO
O
OH
PO
O
OH
P
O
OH
HO
thymidine kinaseguanosine monophosphate kinase
guanosine diphosphate kinase
胸苷激酶 鸟嘌呤核苷单磷酸激酶
Synthesis of Acyclovir
NH
N
O
H2N N
N
O
H2N
Ac
N
N
O
NH
OO CH3
O
H3C
O
N
N
O
H2N
OOH
OO
H3C S OH
O
O
Ac2O
(AcO)2ZnAc
hydrolysis
40% CH3NH2
鸟嘌呤
NH
NN
N
O
OHONH2
N
NN
N
OHONH2
Acyclovir desciclovir
Poor water solubilityPoor absorptionDrug resistance
18 times enhanced solubilityGood absorptionDecreased side effect
Prodrug, be oxidized to acyclovir in vivo
阿昔洛韦 地昔洛韦
Drawback of Acyclovir
oxidation
NH
NN
N
O
OONH2O
O
NH2
Valaciclovir
NH
NN
N
O
OHONH2
HO Ganciclovir
NH
NN
N
O
HONH2
HO
N
NN
N
NH2
Penciclovir
O
OO
O
Famciclovir
伐昔洛韦 更昔洛韦
喷昔洛韦泛昔洛韦
Good GI absortption肠胃吸收好
Higher potencyToxicity ，活性高，毒性大
Stable triphosphate formLonger half-life三磷酸酯稳定，半衰期长
Better bioavailability生物利用度较好
More Acyclovir Related Drugs
Ribavirin 利巴韦林O
HO N
HO OH
NN
H2N
O3 Non-nucleoside antiviral drugs 非核苷类抗病毒药物
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
N
NH
N
O
O
O
AcO N
AcO OAc
O
AcO OAc
AcO OAc
NN
OCH3
O
O
HO N
HO OH
NN
NH2
O
+H+ CH3OH/NH3
Synthesis of Ribavirin
triazole glycoside
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 pol
ymerase, is a DNA Polymerase en
zyme that transcribes single-stran
ded RNA into double-stranded DN
A
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.
3D picture of reverstranscriptase
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 matureprotein 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
3’-azido-3’-deoxythymidineZidovudine齐夫多定
O
HO N
N3
HN
O
CH3
O
AZT
Mechanism of Action: the N3 group at 3’position, instead of OH, inhibitsthe 3’,5’diphosphate ester bond formation, chain terminator
Synthesis of AZT
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
O
HO N
OH
HN
O
CH3
O
O
HO N
N3
HN
O
CH3
O
O
HO N
N
O
CH3
O
FN
FF
Cl LiN3
NH4Cl, DMF
Other NT Inhibitors
O
HO N
N
NH2
O
Zalcitabine, ddC
O
HO N
HN
O
CH3
O
Stavudine, d4 T
SO
HO N
N
NH2
O
Lamivudine, 3TC
O
HO N
N
N
NH
O
Didanosine, ddI
扎西他滨 司他夫定 拉米夫定 去羟肌苷
Purine dideoxynucleosideGiven in advanced HIV infection
Side effect:Painful peripheral neuropathy and pancreatitis
Rapidly absorbedThrough GI tractCombination with DDI, ddC or d4T
Pyrimidine analogueHigh bioavailabilityLow toxicity
Side effect:Pain, tingling, numbnessin hands and feet
Pyrimidine analogHigh bioavailability
Side effects:stomatitis, rash,fever, malaise,arthritis, et al
HO N
N
HN
NH2
Abacavir, ABC阿巴卡韦
University of MinnesotaCollege of pharmacy
Dr. Robert VinceDr. Mei Hua
贰 Nonnucleoside RT Inhibitors (NNRTI) 非核苷类
N N
HN
N
OH3C
Nevirapine 奈韦拉平
From structure-based drug design methodology
Effective against AZT-resistant HIV strainsCombination with ZDV and ddI
Side effect: liver dysfunction and skin rashes
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
叁 HIV Protease Inhibitors 蛋白水解酶抑制剂
HIV protease exists as a dimerEach monomer contains one asparticresidues at the active site
Drugs are designed as transition-statemimetics to align at the active site
1) Peptide
2) Peptide mimetics
3) nonpeptide
Indinavir, 茚地那韦 Nelfinavir, 萘非那韦
沙奎那韦
Ritonavir, 利托那韦
nonpeptide
Protease Inhibitors
Integrase inhibitors
MK-0518, Merck, approved in Sept. 2007
2nd, GS-9139, approved in 2008, Gilead
David Ho （何大一）
Taiwanese American
Time magazine, Man of the Year, 1996
The HAART （鸡尾酒疗法）：highly active antiretroviral therapy
Synergistic effect
1 + 1 > 2
Summary:
Inhibit the earlier stage: amantadine HCl, rimantadine HCl; Interferon, α,β,γ; Inducer: tilorone The Neuraminidase, NA inhibitor, transition state inhibitor
DNA, RNA virusVirus replication cycle
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 Structures Ｉ
NH2
HCl
Amantadine
O
HO N
HN
OH
I
O
O
Idoxuridine
N
NN
N
NH2
O
OH
HOHO
Vidarabine
NH
NN
N
O
OHONH2
NH
NN
N
O
OONH2
O
NH2
H3C
CH3
Acyclovir Valacyclovir
O
HO N
HO OH
NN
H2N
O
Ribavirin
Anti HIV Agents, NNRT inhibitors
O
HO N
N3
HN
O
CH3
O
AZT
O
HO N
N
NH2
O
Zalcitabine, ddC
O
HO N
HN
O
CH3
O
Stavudine, d4 T
SO
HO N
N
NH2
O
Lamivudine, 3TC
O
HO N
N
N
NH
O
Didanosine, ddI
HO N
N
HN
NH2
Abacavir
Indinavir, 茚地那韦Nelfinavir, 萘非那韦
沙奎那韦Ritonavir, 利托那韦
nonpeptide
Protease Inhibitors
Integrase inhibitors
MK-0518, Merck, approved in Sept. 2007Generic name: Raltegravir
2nd, GS-9139, approved in 2008, Gilead
