The controlled production and degradation of cAMP allows for control of many different signaling pathways. cAMP is produced by genetically distinct transmembrane (tmAC) and soluble (sAC) adenylyl cyclases; cAMP is catabolized by phosphodiesterases (PDEs). The relative contributions of sAC and tmAC to cAMP production, and of the PDEs to cAMP catabolism, usually are explored using pharmacological interventions. Because the compounds used to manipulate intracellular cAMP levels must cross cell membranes, they need to partition into lipid bilayers, which raises the question whether they could alter cell function by mechanisms that are unrelated to the changes in cAMP turnover. Indeed, many of these compounds are known to alter the function of other membrane proteins at concentrations that overlap with those used to target cAMP metabolism. Moreover, the concentration range(s) used to obtain the same effect vary widely among experiments, suggesting that these compounds elicit off-target effects that do not involve conventional cAMP signaling pathways. I therefore explored the lipid bilayerperturbing effects of 17 commonly employed modifiers of sAC, tmAC and PDE activity using a GBFA. Twelve compounds perturbed the bilayer at commonly used concentrations. Thus, in addition to their effects on cAMP metabolism, these molecules may alter cell function by being promiscuous modifiers of membrane protein function, meaning they should be used with care. Effects that occur only at concentrations that are three or more times higher than those for half-maximal effect (on the intended target) should be interpreted with caution.
In addition to being important for the interpretation of experiments that explore biological function with small-molecule probes, bilayer perturbation is also an important parameter for drug discovery. In this thesis, I focused on how to improve the development of new malaria therapies, which is necessary due to the perpetual development of resistance to current therapies. The Medicines for Malaria Venture developed the Malaria Box to facilitate the drug development process (and reduce the cost) by providing pharmaceutical company-vetted drug candidates to academicians. To explore whether testing for membrane effects might reduce the expenses required for drug development, I tested the 80 potent compounds from the Malaria Box for bilayer-mediated effects on membrane protein conformational changes (as a measure of literature. However, some significant differences should be further examined in other international teaching environments.
|School:||Weill Medical College of Cornell University|
|School Location:||United States -- New York|
|Source:||DAI-B 75/07(E), Dissertation Abstracts International|
|Keywords:||Antimalarials, Bilayer perturbation, Biological probes|
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