1. Chapter 21 Antiviral Agents
抗病毒药物 nm

2. 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.

3. 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

4. Viral Replication and Transformation 病毒的复制和转化
Attachment
Penetration
Uncoating and transfer of viral DNA to nucleus
Early transcription into viral mRNA
Early translation of viral mRNA into enzymes for viral DNA synthesis
Synthesis of viral DNA and late
transcription of viral mRNA
Late translation of mRNA into viral structural proteins
Assembly of virus particles in nucleus
Budding from nucleus and release of virions

5. 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
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

6. Pharmacokinetics（药代动力学）:
Amantadine （金刚烷胺）
Pharmacokinetics（药代动力学）:
Half-life is 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）

7. Rimantadine （金刚乙胺） Mechanism of Action: Pharmacokinetics:
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 hours
Over 90% of rimantadine doses were absorbed in 3-6 hours

8. Interferon （干扰素）
Interferon are polypeptide hormones, or glycoproteins, MW kD
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
Tilorone， 替洛隆

9. 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

10. Structural derivatives of sialic acid as neuraminidase inhibitors
唾液酸衍生物作为神经氨酸酶抑制剂
6-C ring, prodrug

11. 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
脱氧胸腺嘧啶苷 碘苷
Idoxuridine is a nucleoside containing a halogenated pyrimidine and is an
analogue of thymidine
Acts against DNA viruses

12. 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.
Active form

13. Other Nucleoside Pyrimidine Analogue Inhibitors
阿糖胞苷 氟苷 溴苷
三氟胸苷
Pyrimidine analog
Same mechanism
Anticancer
Same mechanism
Increased potency

14. 2 Purine Analogs （嘌呤核苷类）
Vidarabine
阿糖腺苷
Streptomyces antibioticus
链霉菌
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
Adenine deaminase
腺嘌呤脱氨酶

15. 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

16. 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

17. Mechanism of Action
胸苷激酶
鸟嘌呤核苷单磷酸激酶

18. Synthesis of Acyclovir
鸟嘌呤

19. Drawback of Acyclovir
oxidation
阿昔洛韦
地昔洛韦
18 times enhanced solubility
Good absorption
Decreased side effect
Prodrug, be oxidized to acyclovir in vivo
Poor water solubility
Poor absorption
Drug resistance

20. More Acyclovir Related Drugs
伐昔洛韦
更昔洛韦
Higher potency
Toxicity，活性高，毒性大
Good GI absortption
肠胃吸收好
泛昔洛韦
喷昔洛韦
Stable triphosphate form
Longer half-life
三磷酸酯稳定，半衰期长
Better bioavailability
生物利用度较好

21. Ribavirin 利巴韦林 Mechanism of Action: Non-nucleoside antiviral drugs
非核苷类抗病毒药物
Ribavirin 利巴韦林
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

22. Synthesis of Ribavirin
triazole
glycoside

23. Anti-HIV Agents
抗艾滋病药物
HIV virus
Virus life cycle

24. Anti-HIV targets
1 Reverstranscriptase（逆转录酶） RNA-dependent DNA polymerase, is a DNA Polymerase enzyme that transcribes single-stranded RNA into double-stranded 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.

25. 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.

26. 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

27. 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’-deoxythymidine
Zidovudine
齐夫多定
Mechanism of Action: the N3 group at 3’position, instead of OH, inhibits
the 3’,5’diphosphate ester bond formation, chain terminator

28. Mechanism of Action: AZT is activated in vivo by thymidine kinase,
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

29. Other NT Inhibitors 扎西他滨 司他夫定 拉米夫定 去羟肌苷 Pyrimidine analog
High bioavailability
Side effects:
stomatitis, rash,
fever, malaise,
arthritis, et al
Pyrimidine analogue
High bioavailability
Low toxicity
Side effect:
Pain, tingling, numbness
in hands and feet
Rapidly absorbed
Through GI tract
Combination with
DDI, ddC or d4T
Purine dideoxynucleoside
Given in advanced HIV infection
Side effect:
Painful peripheral
neuropathy and pancreatitis

30. Abacavir, ABC
阿巴卡韦
University of Minnesota
College of pharmacy
Dr. Robert Vince
Dr. Mei Hua

31. Mechanism of Action: Nonnucleoside RT Inhibitors (NNRTI) 非核苷类
From structure-based drug design methodology
Effective against AZT-resistant HIV strains
Combination with ZDV and ddI
Side effect: liver dysfunction and skin rashes
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

32. 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
Peptide
Peptide mimetics
nonpeptide

33. Protease Inhibitors Ritonavir, 利托那韦 沙奎那韦 Indinavir, 茚地那韦
Nelfinavir, 萘非那韦
nonpeptide

34. Integrase inhibitors MK-0518, Merck, approved in Sept. 2007
2nd, GS-9139, approved in 2008, Gilead

35. 1 + 1 > 2 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
> 2

36. Summary: Inhibit the earlier stage:
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

37. Typical StructuresＩ

38. Anti HIV Agents, NNRT inhibitors

39. Protease Inhibitors Ritonavir, 利托那韦 沙奎那韦 Indinavir, 茚地那韦
Nelfinavir, 萘非那韦
nonpeptide

40. Integrase inhibitors MK-0518, Merck, approved in Sept. 2007
Generic name: Raltegravir
2nd, GS-9139, approved in 2008, Gilead