药理学抗病毒药物

药理学抗病毒药物部分内容总结，包括病毒的介绍、病毒生活周期、抗病毒药物、Cytomegalovirus巨细胞病毒 (CMV) drugs等内容。

antiviral

• 病毒的介绍
  • 1.an infectious agent of small size and simple composition that can multiply only in living cells of animals, plants, or bacteria.
  • 2.range in size from about 20 to 400 nanometers (nm) in diameter. By contrast, the smallest bacteria are about 400 nm in size.
  • 3.NO ribosome to translate protein, its life cycle completely depends on host cell.
  • 4.some can be very pathogenic.
  • 5.in short, it is written as “XXV”, “V” stands for virus
• 病毒生活周期
  • 介绍
    • In general, viral life cycle includes:attachment (targeting the correct host cell)—— entry—— replication and biosynthesis (producing viral proteins and genomes)—— assembly (new virion病毒颗粒 forming) ——release (either lytic or non-lytic).
  • 以HIV-1为例
    • A very simplified HIV-1(human immunodeficiency virus type 1) life cycle is shown below: Note that the size of virus is enlarged in order to be seen clearly.
      • • Some viruses do not go into nucleus for genome replication or transcription, instead they reside in cytoplasm. Yet still they use the steps shown in the figure.
  • RNA病毒分类
    • positive-sense XXX
      • the RNA sequence is same as mRNA for translation, usually can be used for direct template for translation (they have 5’cap and 3’ polyA tail);
    • Negative-sense XXX
      • the RNA sequence is reverse-complementary to mRNA sequence. The RNA needs to be transcribed into mRNA first for translation.
• 抗病毒药物
  • 治疗前提
    • Antiviral drugs must have good selectivity on virus over host cells, often target viral entry, exit, or virus-encoded enzymes (eg. HIV-1 protease).
      • 图示
  • 例子
    • Antiviral therapy is now available for herpesviruses疱疹病毒, hepatitis肝炎 C virus (HCV), hepatitis B virus (HBV), papillomavirus乳头状瘤病毒, influenza, and human immunodeficiency virus (HIV).
• Herpes Simplex Virus (HSV)单纯疱疹病毒 and Varicella Zoster Virus水痘带状疱疹病毒 (VZV) drugs
  • 介绍
    • HSV and VZV belong to Herpesvirales疱疹病毒目/Herpesviridae疱疹病毒科/Alphaherpesvirinae假狂犬病病毒.
    • HSV, also known as human herpesvirus疱疹病毒 1 (HHV-1), causes herpes which appears most commonly on genitals外生殖器 or mouth.
    • VZV, also known as Human alphaherpesvirus疱疹病毒 3, causes varicella水痘 (also called chicken pox).
    • HSV and VZV are DNA viruses, they use DNA as genomic material as well as templates for RNA transcriptions, then the RNAs are used as templates for viral protein translation and regulation of viral life cycle.
  • 治疗药物
    • Three oral nucleoside analogs to treat HSV and VZV infections Acyclovir阿昔洛韦（治疗疱疹的药物）；无环鸟苷, Valacyclovir伐昔洛韦 and Famciclovir泛昔洛韦
      • Acyclovir
        • Acyclovir is an acyclic guanosine鸟嘌呤腺苷derivative with clinical activity against HSV-1, HSV-2, and VZV, but it is ~ 10 times more potent against HSV-1 and HSV-2 than against VZV.
        • 作用机理
          • 图示
          • 解说：1Acyclovir is phosphorylated three times inside the cell for its activity. The first modification is done by virus encoded thymidine胸腺嘧啶核苷 kinase and only virus-infected cells can activate acyclovir. 2.Acyclovir triphosphate inhibits viral DNA synthesis by competing dGTP for viral DNA polymerase, resulting in binding to the DNA as an irreversible complex and chain termination following incorporation into the viral DNA.
        • 给药途径
          • The bioavailability of oral acyclovir is low.
          • Intravenous acyclovir is the treatment of choice for herpes simplex encephalitis单纯疱疹脑炎,neonatal新生儿的 HSV infection, and serious HSV or VZV infections.
        • Simplified summary of mechanism of acyclovir and its analogs
        • 抗性
          • Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase.
      • Valacyclovir伐昔洛韦
        • Valacyclovir is the L-valyl 缬氨酰ester of acyclovir. It is rapidly converted to acyclovir after oral administration via first-pass enzymatic hydrolysis in the liver and intestine.
          • 子主题
        • Approved uses of valacyclovir include treatment of first or recurrent genital herpes复发性生殖器疱疹, suppression of frequently recurring genital herpes, and as treatment for varicella水痘and herpes zoster.带状疱疹
      • Famciclovir
        • Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir,喷昔洛韦 an acyclic guanosine analog.
        • After oral administration, famciclovir is rapidly deacetylated and oxidized by first-pass metabolism to penciclovir. It is active in vitro在体外 against HSV-1, HSV-2, VZV, EBV, and HBV.
          • 1.Penciclovir is also available for topical use. 2.Penciclovir triphosphate has lower affinity for the viral DNA polymerase than acyclovir triphosphate.
      • Nucleoside核苷 vs. Nucleotide核苷酸
        • 1.Nucleoside + phosphate = Nucleotide 2.Nucleoside needs to be phosphorylated three times to become nucleotide for DNA or RNA synthesis.
    • Trifluridine (trifluorothymidine)三氟胸苷
      • Trifluridine (trifluorothymidine) is a fluorinated pyrimidine嘧啶 nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia牛痘, and some adenoviruses腺病毒.
      • 结构
      • 机制
      • 注意
        • Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use.
      • 用途
        • Effective in treating keratoconjunctivitis角膜结膜炎 and recurrent epithelial keratitis角膜炎 due to HSV-1 or HSV-2.
    • Docosanol廿二（烷）醇
      • Docosanol is a saturated 22-carbon aliphatic脂肪族 alcohol that inhibits fusion between the plasma membrane and the HSV envelope包膜, thereby preventing viral entry into cells and subsequent viral replication.
      • Topical docosanol 10% cream is available without a prescription.
• Cytomegalovirus巨细胞病毒 (CMV) drugs
  • 介绍
    • CMV is a DNA virus, belongs to herpesviridae疱疹病毒科 family, betaherpesvirinae贝塔疱疹病毒科 subfamily.
    • CMV is a common virus that can infect almost anyone. Once infected, your body retains the virus for life.
    • Most people don't know they have CMV because it rarely causes problems in healthy condition.
    • People at greater risk of signs and symptoms of CMV include:
      • Newborns infected with CMV before birth (congenital先天的 CMV).
      • Infants婴儿 who become infected during birth or shortly afterward (perinatal出生前后的 CMV).
      • People with weakened immune systems, for example due to organ transplant or HIV infection.
    • Treatment includes (1) oral valganciclovir左戊韦 and (2) ganciclovir加可韦 intraocular眼内的 implant植入物
  • 治疗药物
    • Ganciclovir更昔洛韦
      • Ganciclovir is an acyclic guanosine鸟嘌呤核苷 analog that requires activation by triphosphorylation before inhibiting the viral DNA polymerase.
      • Initially modified by virus-specified protein kinase UL97 in CMV-infected cells.
      • Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, HHV-6, and HHV-8. Its activity against CMV is much stronger than that of acyclovir.
      • Resistance to ganciclovir increases with duration of usage, commonly found in mutation of UL97 gene.
      • 结构
      • 作用机制
    • Valganciclovir缬更昔洛韦
      • Valganciclovir is an L-valyl缬氨酰 ester prodrug of ganciclovir.
      • After oral administration, both diastereomers非对映体 are rapidly hydrolyzed to ganciclovir by esterases酯酶 in the intestinal wall and liver
      • Valganciclovir is indicated for the treatment of CMV retinitis视网膜炎 in patients with AIDS and for the prevention of CMV disease in high-risk kidney, heart, and kidney-pancreas胰腺 transplant patients.
      • 结构
    • Cidofoviris
      • Cidofoviris a cytosine胞嘧啶 nucleotide核苷酸 analog with in vitro activity against CMV, HSV-1, HSV-2, VZV etc.
      • As a potent inhibitor of and as an alternative substrate for viral DNA polymerase.
      • Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus腺病毒, human papillomavirus乳头瘤病毒, and poxvirus痘病毒 infections.
      • 结构
    • Foscarnet膦甲酸
      • 介绍
        • Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate焦磷酸盐 analog that directly inhibits herpesvirus疱疹病毒 DNA polymerase, RNA polymerase, and HIV reverse transcriptase.
      • 结构
        • pyrophosphate
      • 机制
        • Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates
      • 给药方式
        • Foscarnet is available in an intravenous formulation only.
      • 用途
        • Foscarnet is effective in the treatment of CMV retinitis, CMV colitis结肠炎, CMV esophagitis食管炎, acyclovir-resistant HSV infection, and acyclovir-resistant VZV infection.
      • 抗性产生
        • Resistance to foscarnet in HSV and CMV isolates is due to point mutations in the DNA polymerase gene.
• These drugs are similar in mechanisms of action, clinical use and body tolerance.