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Controlling Sulfuryl‐Transfer In Vivo One Compound at a Time
Author(s) -
Cook Ian,
Feng Lei,
Wang Hua,
Kopp Felix,
Wang Ting,
Wu Peng,
Marlow Florence,
Leyh Thomas
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb470
Subject(s) - in vivo , chemistry , agonist , receptor , pharmacology , lead compound , ligand (biochemistry) , biochemistry , in vitro , biology , genetics
Sulfonation is a reversible modification that regulates the binding of endogenous and xenobiotic small‐molecules to receptors, controls their half‐lives and is intimately linked to human disease and drug efficacy. In humans, these reactions are catalyzed by a small (13 member) family of broad‐specificity enzymes, the cytosolic sulfotransferases (SULTs). Here, molecular principles of SULT and nuclear‐receptor ligand‐specificity are used to create, for the first time, a design strategy that is capable of preventing the sulfation of a single compound in vivo without inhibiting SULTs or significantly altering the receptor‐binding functions of the compound. Unlike classical inhibition approaches, this new strategy prevents sulfonation without inhibiting SULTs and thus maintains their homeostatic functions. The strategy is demonstrated for the nuclear‐receptor family in an ex‐vivo structure‐activity study based on the scaffold of raloxifene (Evista ® ) ‐ an FDA‐approved nuclear‐receptor agonist – and is shown to dramatically enhance the efficacy of apomorphine (an FDA‐approved dopamine‐receptor agonist) in zebrafish. The results indicate that sulfuryl‐transfer and its attendant biology can now be controlled in vivo on a compound‐by‐compound basis. These concepts are expected to lead to new highly specific in vivo probes of sulfuryl‐transfer biology, improvements in drug design and substantial enhancements in the efficacy of numerous FDA approved drugs.