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56 Cards in this Set
- Front
- Back
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What are the steps in the viral life cycle that serve as targets for anti-viral therapy?
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1) Early stages - attachment, penetration, uncoating
2) Replication of the viral nucleic acid 3) Protein synthesis 4) Maturation (processing, assembly) and release of virus progeny |
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What is Amantadine?
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Clinically called Symmetrel. A synthetic amine that blocks both uncoating and assembly.
Effective against influenza A, but not B Targets the M2 protein - viral ion channel |
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What drug blocks both uncoating and assembly, and is effective against Influenza A only?
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Amantadine
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How does Amantadine work?
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The target is the M2 protein - viral ion channel
The drug blocks the channel, causing a rise in pH in the endosomes that contain the virus - prevents conformation change in HA which is required for fusion of the viral envelope with the endosomal membrane - prevents release of the viral RNP... ***It prevents uncoating*** |
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When is Amantadine effective?
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It is only effective prophylactically, if given before infection or at a very early stage of infection.
Amantadine is used as an alternative for vaccination in the elderly and for people with severe diseases that were not vaccinated. It can also be used during appearance of a new influenza strain that was not included in the vaccine |
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What is the most important drug against herpetic infections?
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Acyclovir (Zovirax)
A nucleoside analogue of guanosine |
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What is used for HSV infections?
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Adenine Arabinoside - ara-A
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How does Adenine Arabinoside work?
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Preferred inhibition of DNA synthesis:
~Inhibition of the viral DNA-dependent DNA pol. 40-fold more than the cellular polymerase. ~Incorporation of ara-A into the synthesized viral DNA - creation of faulty DNA |
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What is the first drug used successfully against herpes encephalitis?
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Ara-A
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What are the problems of Ara-A
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Low solubility and high toxicity. It is not efficient enough in discriminating viral and host DNA polymerases - toxic to dividing cells in the bone marrow and GI tract
****IT DOES NOT PREVENT RECURRENT INFECTIONS |
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What drug is effective against herpes keratitis?
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Ara-A
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What drug is a nucleoside analogue of guanosine?
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Acyclovir
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What is the mode of action of acyclovir?
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Active form of the drug is acyclovir-triphosophate. The herpesvirus thymidine kinase (TK) efficiently phosphorylates acyclovir, whereas cellular TKs are much less efficient.
Acyclovir-triphosphate inhibits herpes DNA pol more effectively than it does the cellular DNA pol alpha Acyclovir triphosphate also serves as a substrate for the polymerase - it competes with dGTP for incorporation into the viral DNA. This leads to **chain termination** because acyclovir lacks the 3' hydroxyl group required for chain elongation. Highly selective drug. Good solubility. Low toxicity. |
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What is the advantage of Acyclovir over Ara-A?
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Acyclovir preferentially inhibits viral DNA pol over host DNA pol
Good solubility Low toxicity |
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What activates Acyclovir so that it can be incorporated into viral DNA?
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Thymidine Kinase
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What are the uses of Acyclovir?
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Drug of choice for herpes encephalitis. Should be given as early as possible.
Treatment of genital herpes - shortens the duration and alleviates the symptoms. It does not prevent recurring infections Efficient against disseminated HSV infections in immunocompromised patients Efficient against disseminated VZV infections, but higher doses are required |
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What is the drug of choice for herpes encephalitis?
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Acyclovir
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What mediates herpes resistance to Acyclovir?
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Mutations in TK or in DNA pol.
Human herpes viruses that do not possess a gene coding for TK are only susceptible to acyclovir at very high doses. Susceptibility of viral DNA pol to acyclovir-triphosphate varies between different herpesviruses |
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What is the first drug for treatment of CMV infections?
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Gancyclovir
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What anti-viral is a guanine analog?
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Gancyclovir
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What disease is Gancyclovir used against?
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Severes diseases caused by CMV - mainly in immunocompromised patients
AIDS patients Transplant recipients Drug is given intravenously |
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How does Gancyclovir work?
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A CMV kinase phsphorylates and activates the drug, which is then incorporated into viral DNA and causes chain termination.
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What is the mode of actionof AZT?
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AZT is phosphorylated to its active form, AZT-ppp by cellular enzymes
AZT-ppp binds reverse transcriptase (RT) 100-fold more than the cellular DNA pol. alpha AZT-ppp is incorporated into DNA (instead of TTP) and causes chain termination In addition, AZT-p competes for the cellular TK, resulting in depletion of the intracellular pool of TTP |
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What are the uses for AZT?
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Slows AIDS progression, but cannot cure it: suppresses viral replication, but does not eliminate the viral genome.
Early treatment probably postpones the progression from asymptomatic to symptomatic infection. Start treatment when signs of reduced function of the immune system appear ***Toxic to bone marrow ***Emeregence of resistant strains |
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How do viruses become resistant to AZT?
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Mutations accumulate in Reverse Transcriptase
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What anti-viral is toxic to bone marrow?
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AZT
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What is the host side effect of AZT?
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Toxicity in bone marrow
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What are RT blockers other then AZT?
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ddC - dideoxydytidine
ddl - dideoxyinosine **Do not show cross resistance with AZT |
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What is the recommended treatment regimen for AIDS?
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To minimize drug resistance (RT blockers), combined chemotherapy with two drugs that block RT.
HAART - Highly Active Anti-Retroviral Therapy - includes also protease inhibitors or fusion inhibitors. |
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What is HAART?
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HAART - Highly Active Anti-Retroviral Therapy - includes also protease inhibitors or fusion inhibitors.
Idea is to give multiple drugs to minimize resistance and have synergistic effect |
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How does Foscarnet work?
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An analog of pyrophosphate. Inhibits DNA polymerase in a non-competitive manner. Is not incorporated into the synthesized DNA chain. Binds the polymerase in the pyrophosphate binding site
Active against HSV and CMV |
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What viruses is Foscarnet active against?
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HSV and CMV
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What are the problems with Foscarnet?
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It accumulates in bone and is toxic to the kidneys.
It is only used in life threatening infections. |
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What are the groupings of anti-HIV drugs?
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Nucleoside analogs
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Protease Inhibitors Viraul Fusion Inhibitors |
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What are the characteristics of Interferon?
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**The first line of defense against viral infections before the immune system is mobilized
1) A group of proteins that inhibit virus multiplication. Some are glycoproteins 2) Synthesized in the cells in response to virus infection or to other inducers. IFNs are made de novo in cells - **ARE NOT PREFORMED** IFN production requires mRNA and protein synthesis 3) Acid-resistant 4) 166 AA size. Secreted as a smaller protein of 143-146 AA 5) IFNs are not specific only to the inducing virus, but create a general "anti-viral state". they are very potent: up to 50 molecules per cell are sufficient for this effect. 6) IFNs inhibit the formation of both RNA and DNA containing viruses - act against a common function, namely the translation of mRNAs. 7) Host-species specific. This specificity results from the specificity of the IFN-cell-surface receptor interactions. Biologically activity is usually proportional to binding affinity. |
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Where is IFN-alpha formed? What is a unique feature of IFN-alpha?
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Primarly in leukocytes or lymphoid cell lines.
Multigenic - at least 15 genes with 85-90% homology. The product IFNs have cross-reactivity. |
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Where is IFN-beta formed? What are it's unique features?
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Synthesized primarily in fibroblasts.
Coded by one gene. Exhibits 30% homology with IFN-alpha More labile. Has a far lower antiviral activity than IFN-alpha |
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Where is IFN-gamma formed? What are it's unique features?
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***Called Immune Interferon
Formed in stimulated lymphocytes. Has importance in modulating activity of the immune system. Coded by one gene. |
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Where are the different IFNs formed?
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Alpha - Leukocytes or Lymphoid cell lines
Beta - Fibroblasts Gamma - Stimulated Lymphocytes |
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What is important in the induction of IFN production?
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dsRNA
The most important inducer is viral infection. In general, RNA-containing viruses are good interferon inducers, while DNA containing viruses are poor inducers (exception poxviruses) IFN genes are normally repressed. Infection causes repressor to stop, and transcription of IFN genes. Different infectious agents stimulate activation of different IFN genes. |
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What is the key molecule in IFN production?
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dsRNA
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How do IFNs work?
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They induce a set of new proteins which affect virus production. IFNs do not act directly on the virus.
1) Effects exerted on cells at the plasma membrane via specific receptors 2) IFN binds receptor, triggering a signal transduction pathway that activates several genes. These genes contain Interferon Response Sequence (IRS). The protein products of these genes are called Interferon Regulated Proteins (IRPs) |
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How do IRPs work?
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Interferon Regulated Proteins
~Antiviral activity requires virus products like dsRNA ~Inhibition of different virus families is caused by different mechanisms, involving different IFN-induced IRPs ~Different stages in the virus life cycle are inhibited - blocking virus multiplication at more than one stage is more effective |
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What is the 2-5(A) synthetase / RNase L pathway?
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IFN induces the synthesis of 2-5A synthetase, the enzyms is INACTIVE
**dsRNA activates the enzyme and 2-5A is formed. The source of dsRNA is the naked replicative intermediates of (+) RNA viruses The replicative intermediates of (-) RNA viruses and dsRNA viruses ARE NEVER NAKED, this mechanism applies only to the positive strand virus. 2-5A activates RNase L. The ribonuclease cleaves viral ssRNA, thus preventing translation of viral proteins **The specificity to the viral ssRNAs is not clear. Perhaps the induction by viral dsRNA is localized near viral replicative centers This pathway inhibits multiplication of s.s. RNA (+) viruses |
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What is ds RNA-dependent protein kinase?
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IFN induced protein
IFN induces ds RNA-dependent protein kinase (PKR) = elF-2 kinase. **This kinase is normally active** The enzyme is activated by infection with viruses such as EMC, reovirus, VSV, or vaccinia, or by minute amounts of dsRNA, resulting in autophosphorylation The active PKR phosphorylates a subunit of a translation initiation factor: elF2-alpha. The phosphorylated factor is inactive - **Preventing protein synthesis** - **Preventing synthesis of viral componenets** *****Several viruses encode inhibitors of PKR, rendering them resistant to IFN (Adenovirus) |
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What is ADAR?
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An enzyme involved in purine metabolism. It is needed for the breakdown of adenosine.
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What is the role of ADAR in viral infection?
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dsRNA is the ADAR substrate, and not a regulatory factor.
RNA editing: C6 deamination of adenosine to inosine. Changes in RNA coding capacity. |
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What are MX proteins?
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GTPases involved in endocytosis and vesicle transport.
Inhibit many RNA viruses (Orthomyxo, Paramyxo, Rhabdo, Bunya, Toga) Associate with viral nucleocapsids and inhibit nuclear transport and viral genome transcription |
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What is the virus-IFN equilibrium?
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Viral inhibition of IFN signaling.
In nature, equilibrium is maintained between viruses and the IFN system. In the lab, high doses of IFN shut off viral replication. High viral loads render IFN ineffective |
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What signaling pathways do IFN use?
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Jak/STAT pathway
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What are viral strategies to inhibit the IFN system?
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Inhibition of IFN synthesis
Decoy receptors Inhibition of IFN signaling - Polyoma virus T-antigen binds Jak1, Adenovirus E1A disrupts transcription complexes (ISGF3 and co-activators) Interference with functions of interferon-induced proteins - Inhibition of PKR, RNase L. |
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How does commercial production of IFN take plase?
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Induction of leukocytes in tissue culture - limited amount of produced IFN
Prudction of recombinant IFN by genetic engineering - the current method |
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Why is IFN a good candidate for treatment of viral disease?
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1) Large spectrum of action
2) Participates in the natural healing process 3) A weak antigen - no immune response |
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What are the clinical uses of IFN treatment?
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1) Herpes infection
2) Various forms of hepatitis 3) In recent years, IFN is used to arrest and eliminate chronic infections of HBV, HCV, herpesvirus zoster, and CMV with modest success |
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What are the non-anti-viral functions and clinical uses of IFN?
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IFN affects cellular functions related to growth, differentiation and immunoregulation.
***IFN possesses an antiproliferative activity which is used in treatment of some human cancers - mainly tumors that originate from mature B cells and plasma cells, such as Hair cell leukemia, Chronic myelocytic leukemia, etc. |
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What is a non viral use of IFN?
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Treatment of some human cancers, mainly tumors that originate from mature B cells and plasma cells
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