LECTURE 5 - Drug discovery Examples for class AIDS protease...

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Unformatted text preview: Drug discovery Examples for class: AIDS: protease inhibitors Alzheimer’s: BACE inhibitors Blood coagulation: Heparin and coumarin Drug discovery Examples for class: AIDS: protease inhibitors in clinic-background about AIDS-understanding HIV protease-actual drugs Alzheimer’s: BACE inhibitors (we wish)-methodology of drug development Blood coagulation: Heparin and coumarin-more serine proteases-advantage of multiple approaches HIV and AIDS Aquired immunodefciency syndrome (AIDS)-caused by human immunodefciency virus (HIV)-5 - 10 year latency period-Invade CD4 + T lymphocytes-in late stages, patients are susceptible to opportunistic inFections-the only major epidemic caused by a previously unknown agent in 20th century- >40 million people living with the disease worldwide, having killed >25 million thus Far-still no known cure or vaccine-however, there are MANY treatments: many patients can live with it-¡ocus here on protease inhibitors…. HIV and AIDS • 72 glycoprotein complexes on lipid membrane • Gp120 and gp41 transmembrane protein • Inside p17 matrix and p24 core antigen protein • Two copies of RNA • Reverse transcriptase enzyme • Nucleoprotein p7 Selected steps in HIV life cycle HIV-1 polyproteins HIV-1 protease cleavage sites (cleavage occurs during maturation) Can we design peptido-mimetics? HIV protease: like pepsin HIV protease is similar to other aspartic proteases, like pepsin HIV protease: mechanism Different mechanism than serine proteases like chymotrypsin-no covalent intermediate-however, still have a tetrahedral intermediate! HIV protease: structure open closed (with inhibitor bound) HIV protease: H-bonding in modeled substrate Many backbone interactions, not so many specifc side-chain interactions HIV protease: tetrahedral mimics and drugs 1...
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This note was uploaded on 02/25/2010 for the course CHEM 4611 at Colorado.

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LECTURE 5 - Drug discovery Examples for class AIDS protease...

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