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DRUG INVENTION AND PHARMACEUTICAL INDUSTRY Drugability refers to the ease with which the function of a target can be altered in the desired fashion by a small organic molecule. X-ray crystallography offers the most detailed structural information if the target protein can be crystallized with the lead drug bound te it. Nuclear magnetic resonance (NMR) studies of the drug-receptor complex also can provide useful information (albeit usually at lower resolution), with the advantage that the complex need not be crystallized. —Insulin was introduced into clinical medicine for the treatment of diabetes following the experiments of Banting and Best in 1921. ~ Insulins purified from porcine or bovine pancreas are active in humans, although antibodies to the foreign proteins are occasionally problematic. Growth hormone, used to treat pituitary dwarfism, exhibits mere stringent species specificity. Only the human hormene could be used after purification from pituitary glands harvested during autopsy, and such use had its dangers—some patients who received the human hormone developed Creutzfeld+- Jakob disease (the human equivalent of mad cow disease), a fatal degenerative neurological disease caused by prien proteins that contaminated the drug preparation. -Through gene cloning and the production of large quantities of proteins by expressing the cloned gene in bacteria or eukaryotic cells, protein therapeutics now use highly purified preparations of human (or humanized) proteins. - Rare proteins can be produced in quantity, and immunglegical reactions are minimized. ~ Proteins can be designed, customized, and optimized using genetic engineering techniques. Other types. of macromolecules may also be used therapeutically. For eg, antisense oligonucleotides are used to block gene transcription or translation, as are siRNAs. ~ Proteins used therapeutically include hormones; growth factors (eg, erythropoietin, G-CSF); cytokines; and a ne. of meneclonal antibodies used in the treatment of cancer and autoimmune diseases. - Murine meneclonal antibodies can be “humanized” (by substituting human for mouse amine acid sequences). ~ Alternatively, mice have been engineered by replacement of critical mouse genes with their hurnan 
