Identification of synthetic phosphatidylserine translocases from a combinatorial library prepared by directed split-and-pool synthesis.
Simple sulfonamide and amide derivatives of tris(2-aminoethyl)amine (Tren) are known to promote the translocation or flip-flop of phosphatidylcholine, but not phosphatidylserine, across bilayer membranes. This paper describes the synthesis of a 300-member, spatially encoded library of Tren derivatives with appended peptide--sulfonamide and peptide--urea arms. The library was synthesized using the Encore method with SynPhase lanterns as the solid support. A high-throughput assay was developed to screen individual members of the library for an ability to translocate a fluorescent NBD derivative of phosphatidylserine across vesicle membranes. Several lead compounds were identified, and one was synthesized independently to confirm its high phosphatidylserine translocation activity.
Shukla
Rameshwer
R
Department of Chemistry and Biochemistry and the Walther Center for Cancer Research, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Sasaki
Yoshihiro
Y
Krchnák
Viktor
V
Smith
Bradley D
BD
D020650:Combinatorial Chemistry Techniques; D005456:Fluorescent Dyes; D008081:Liposomes / Q000378:metabolism; D018716:Molecular Mimicry; D010718:Phosphatidylserines / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology
D005456:Fluorescent Dyes; D008081:Liposomes; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins