title: N-linked peptidoresorc[4]arene-based receptors as noncompetitive inhibitors for α-chymotrypsin.
abstract: This paper deals with the design, synthesis, and evaluation of a new series of receptors for protein surface recognition. The design of these agents is based around the attachment of four constrained dipeptide chains onto a central resorc[4]arene scaffold. By varying the sequence, nature, and stereochemistry of the chains we prepared anionically functionalized N-linked peptidoresorc[4]arenes 12, 13, and 17 by Pd/C-catalyzed hydrogenation of the corresponding benzyl esters 10, 11, and 16. From this family of receptors we have identified noncompetitive inhibitors of α-chymotrypsin (ChT), which function by binding to the surface of the enzyme in the neighborhood of the active site cleft (K(i) values ranging from 12.4 ± 5.1 μM for free carboxylic acid (+)-12b to 0.76 ± 0.14 μM for benzyl ester (-)-16a). For anionically functionalized receptors 12, 13, and 17 the ChT inhibition is based essentially on electrostatic interaction, and the bound enzyme can be released from the resorcarene surface by increasing the ionic strength, with its activity almost completely restored. For receptors with terminal benzyl ester groups (10 and 16) a hydrophobic network can be suggested.
authors.affiliation: Dipartimento di Chimica e Tecnologie del FarmacoSapienza Università di Roma, Roma, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: D'Acquarica
authors.forename: Antonella
authors.initials: A
authors.lastname: Cerreto
authors.forename: Giuliano
authors.initials: G
authors.lastname: Delle Monache
authors.forename: Fabiana
authors.initials: F
authors.lastname: Subrizi
authors.forename: Alberto
authors.initials: A
authors.lastname: Boffi
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
authors.forename: Stefano
authors.initials: S
authors.lastname: Forli
authors.forename: Bruno
authors.initials: B
authors.lastname: Botta
mesh_terms: D000818:Animals; D047250:Calixarenes / Q000737:chemistry*; D020134:Catalytic Domain; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry*; D009994:Osmolar Concentration; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D012709:Serum Albumin / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D010456:Peptides, Cyclic; D010636:Phenols; D011480:Protease Inhibitors; D012709:Serum Albumin; C121325:calix(4)arene; D047250:Calixarenes; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D009584:Nitrogen