POP4.6.11

POP4.6.11 - 4.6.11POP -ribosome translates a single mRNA...

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4.6.11—POP -ribosome translates a single mRNA into thousands of copies of protein -for intracellular targets—current therapeutics inhibit allosteric sites on these protein targets—small molecule therapeutics is what is used because they can passively diffuse across the cell MV because they have a Log P value which is slippery/oily enough to get through MB -by the time mRNA has translated lot of proteins, you have a lot of proteins to interact with so RNA interference regulates Gene expression -in RNA interferenece, smamll hhair pin loops that are untranslated are exported into the cytoplasm where DICER cleaves them into 22-23mer with 3’ overhangs and TRBP loads it into the catalytic unit cauused RISC—and guide strand is retained at Argonaut to tralationally inhibit mRNA from interacting with the ribosome—degrade it from 3’ end from 5’ end --we can take advantage of this therapeutically by synthesizing siRNAs that essentially mimic miRNAs—they havevery good EC50—TRBP will load it onto Argonaut 2 (there are 4 family members, therapeutically we want to target ago 2) it will cleave mRNA at a very speicifc location—yo ucan completely kill the mRNA from ever being translated— in comparison from mopping up the watter after broken dam—now you just need to target 1 but it comes with a lot of problems too -from a cancer point of view—small molecule therapeutics have a very small number of targets in the genome—specifially inhibit catalytic sites or alter its activity up or down -RNAi—turns 1000 at best to 28000—you can set up synthetic lethal RNA –when knocked down gene in a normal cell have no effect, and make a second siRNA and have no effect when knocks own Gene Y—but together, causes tumor cell death! siRNA can evolve the drug as tumor genetics evolves -identify the tumor and see that there are 20 oncogenes that are mutated and activated so you make siRNAs against most active 2 oncogenes, treat those patients , induce synthetically letal RNA response ONLY in tumor ells, then it brings tumor burden below detection—you don’t die fro primary tumor, you die from recurrent disease usually so by stopping and treating the recurrent disease, can improve survival!—tumor genetics evolve so that is a problem—sequence and reidentify the target oncogenes and likely siRNA#1 target sequence is going ot mutated so youredesign the drug to goafter the mutation and the second one that is new, you go after the 3 rd oncogene and now it goes below the level of detection again—and manage the patients cancer for the rest of hteir life—if there is not an approved therapeutic, they can evolve the drug—it’s the only thing that can be evolved to treat the evolving tumor genetics—this is THOUSANDS of new therapeutics (maybe) drug= short interfering RNA—the passenger strand is the sense strand and guide strand is (anti-sense strand) -no one that is dealing with siRNA to be involved with anti-sense strand so they changed the name to guide strand
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This note was uploaded on 09/14/2011 for the course PHARM pp taught by Professor Staff during the Spring '11 term at UCSD.

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POP4.6.11 - 4.6.11POP -ribosome translates a single mRNA...

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