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24 Cards in this Set
- Front
- Back
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What is the first thing that must be done to enabble drug discocery/dev'l?
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Must identify a target
Good targets: viral enz or ptns that don't have a cellular counterpart (i.e. RT) Target an enz so that teh virus can't replicate. A very specific drug won't harm the host |
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What does assay dev'l facillitate?
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-screening of large libraries of cmpds that can inhibit the enz
-get crystal structures and see if the enz will co-crystallize with the inhibitor to see if it can be improved -functional assays of enz (binding experiments) |
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What are the pahses of a clinical trial?
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Phase 1: test drugs at dif doses. Done on healthy volunteers and test to see if there is any toxicity effects
Phase 2: Test potentcy (efficacy) of drugs. Use a large group (cohorts) and try to find the right dose to assess the efficacy Phase 3: Very large trial with many, many ppl. Look for complication and long-term effects. Try to have an end pt of study: sustained biological response |
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What is the main problem with anti-viral drugs?
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Resistance
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What happens when a virus develops resistance to your drug?
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-Go back to drug development and make a secondary generationdrug cmpd which is better then the first (with 2nd generation drugs, have discovered the mechanism of resistance of the virus)
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What are set points? What are they used for?
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Can be viral load and the amount of CD4+ T-cells (i.e for HIV infection)
-Set points are used to assess and predict how a patient will respond to therapy |
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What was the first drug developed against HIV?
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AZT: primary nucleoside inhibitor, but the virus quickly dev'p resistance, since it was only used as monotherapy
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What must first be done before developing a drug?
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-Must ID the target, .: must first figure out the replication cycle
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What are targets of HIV drugs?
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-Reverse transcriptase
-Integrase -Maturation assembly process |
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Why was reverse transcriptase targetted?
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Was the 1st target of HIV drugs, RNA--> DNA Incorporates nucleotides
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What are the 2 ways to inhibit reverse transcription? Describe.
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1) Nucleoside Analogue RT Inhibitors (NRTI): Active vs HIV-1 and 2.
-all have common feature like AZT, d4T and 3TC -all lack 3'OH, which is acquired by the attack of the incoming nucleotide. When these are incorporated, there's isn't an OH to be attacked .: Chain Termination 2)Non-Nucleoside Analogur RT Inhibitors (NNRTI): Active vs HIV-1 only -aren't nucleosides so they don't compete (non-competitive inhibitors) -bind hydrophobic pockets away from the active site |
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What are some of the drugs used now to inhibit RT?
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Atriola: combinesnucleoside and non-nucleoside inhibitors
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What do protease inhibitors do?
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Bind proteases (i.e. Indinavir/Ritonavir)
-competitive inhibitor that binds to the active site and blocks it sothat the substrate can't bind and be processed |
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How is a protease inhibitor developed?
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Start with a peptide that mimics the precursor peptide that will be cleaved.
Try to make this drug better by crystallizing it |
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What is the best way to reduce viral load?
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Combination therapy
Use a protease inhibitor + an RT inhibitor (i.e Ritonavir +AZT or 3TC) |
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What is special abou Ritonavir?
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-Can boost Protease Inhibitors
-Cellular enz can degrade PIs and diminish their potency over time. -> Ritonavir can bind these enz and prevent their fct -Co-administration of Ritonavir can enhance the potency of other PIs |
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How is CD4 levels related to a decrease in viral load?
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Not directly proportional
Just cuz viral load is dec, doesn't mean that CD4 cell lvls will inc |
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What is the differnce between anti viral HIV treatment and antiviral HCV treatment?
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Anti-HIV: Eradication of HIV not realistic right now. Goal is to maximes suppression of HIV replication. HAART can reduce plasma RNA lvl to conc below limit of detection
Anti-HCV: Eradication of HCV IS possible. Pegylated-IFN and Ribavirin (but not everyone responds at the same lvl). Problem is to come up with drugs that are specifically targetting viral ptns |
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What is the Replicon system?
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Can look at replication of virus in cell
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Which ptns are considered targets for HCV therapy?
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All of the NS ptns
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What needs to be taken into account when doing combination therapy?
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Drug-drug interactions
Make sure the drugs don't reduce each other's levels or have negative effects on the patient |
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Why does HIV treatment fail?
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-Drug-drug interactions
-Drug resistance -Nonadherence (patient doesn't stick with the drug regime) -Pharmacokinetics -WeakHAART regime -Aggresive HIV infection |
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How is resistance to drugs dealt with?
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Look for genotypic and phenotypic resistance assays. Look for a mutation in pre-existing genome to chose which drugs to use and avoid
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What are the 3 new clases of drugs vs HIV?
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-Fusion Inhibitors
-Entry Inhibitors: interfere with coreceptors -HIV integrase strand transfer inhibitors: select for mutations in integrase Can use all these drugs in combination, if there is no cross resistance |
