By Allen B. Reitz
Quantity five of Advances in Medicinal Chemistry includes 4 fascinating and distinct money owed of the shut interface among man made chemistry, structure-activity relationships, biochemistry, and pharmacology. In bankruptcy 1, there's a finished survey of the immunophilin region in particular focussing on neuroregenerative functions within the relevant frightened method. In bankruptcy 2, there's an summary of the improvement of a effective analgesic compound that works through modulation of neuronal nicotinic acetylcholine receptors. In bankruptcy three, there's a description of dopamine D-2 autoreceptor partial agonists as power treatment for the remedy of schizophrenia. In bankruptcy four, there's a precis of the winning application within which effective non-peptide inhibitors of HIV protease from the AIDS virus have been built.
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A recent report that both FKBP12 and cyclophilin can interact with the V3 loop of the HIV-1 coat protein (gpl20) also suggests a role for immunophilins in HIV pathogenesis. 176 As the brief review above demonstrates, immunophilins play roles in a wide variety of cellular processes. In a subsequent section, we will discuss in some detail the presence and therapeutic utility of immunophilins in the mammalian nervous system. First, however, we will describe the structural biology of the PPIases. 24 GREGORY S.
1R, and interacts with FKBP13 at its carboxy-terminal domain. A His-Pro sequence at the carboxy terminus was shown to be necessary for FKBP12 binding. Experiments with antibodies against FKBP13 suggested that FKBP13 was present in red blood cells (which lack an ER), supporting a non-ER role for this immunophilin. Several published studies provide some insight into the developmental role of immunophilins by analyzing the temporal profile of immunophilin expression. In chick embryos, FKBP12 was expressed by day 4 and was primarily associated with cardiomyocytes and osteo-chondrocytes.
237 When rat brain homogenates were monitored for [3H]FK506 binding, Snyder's group found that FKBP12 levels in the brain were much higher than in immune tissues, nearly 50-fold greater. 238 This discovery was made just at the time of the literature reports on calcineurin as the target of the FKBP12-FK506 and cyclophilin-CsA 50 GREGORY S. HAMILTON and CHRISTINE THOMAS complexes. Using autoradiography, immunohistochemistry, and in situ hybridization, the Hopkins group determined the brain localization of FKBP12, cyclophilin A, and calcineurin.
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