Multivalency represents an appealing option to modulate selectivity in enzyme inhibition and transform moderate glycosidase inhibitors into highly potent ones. The rational design of multivalent inhibitors is however challenging because global affinity enhancement relies on several interconnected local mechanistic events, whose relative impact is unknown. So far, the largest multivalent effects ever reported for a non-polymeric glycosidase inhibitor have been obtained with cyclopeptoid-based inhibitors of Jack bean α-mannosidase (JBα-man). Here, we report a structure-activity relationship (SAR) study based on the top-down deconstruction of best-in-class multivalent inhibitors. This approach provides a valuable tool to understand the complex interdependent mechanisms underpinning the inhibitory multivalent effect. Combining SAR experiments, binding stoichiometry assessments, thermodynamic modelling and atomistic simulations allowed us to establish the significant contribution of statistical rebinding mechanisms and the importance of several key parameters, including inhitope accessibility, topological restrictions, and electrostatic interactions. Our findings indicate that strong chelate-binding, resulting from the formation of a cross-linked complex between a multivalent inhibitor and two dimeric JBα-man molecules, is not a sufficient condition to reach high levels of affinity enhancements. The deconstruction approach thus offers unique opportunities to better understand multivalent binding and provides important guidelines for the design of potent and selective multiheaded inhibitors.
Abstract Invited for the cover of this issue are the groups of Giorgio Della Sala at the Università degli Studi di Salerno and Luigi Cavallo at the King Abdullah University of Science and Technology. The image depicts the transition state involved in the crown ether catalyzed arylogous Michael reaction of phthalides. Read the full text of the article at 10.1002/chem.201900168 .
Head-to-tail cyclization of linear oligoamides containing 4-benzylaminomethyl-1H-1,2,3-triazol-1-yl acetic acid monomers afforded a novel class of "extended macrocyclic peptoids". The identification of the conformation in solution for a cyclodimer and the X-ray crystal structure of a cyclic tetraamide are reported.
Abstract Multivalency represents a powerful approach to increase the inhibition potency of moderate glycosidase inhibitors. Regarding the key role of catalytic glycoside hydrolysis in biology, understanding the molecular mechanisms and origin of the multivalent inhibitory effect is of great interest and presents a fascinating playground for theoretical studies. Our teams have recently dissected key processes of multivalent glycosidase inhibition through the use of different neoglycoclusters based on deoxynojirimycin (DNJ) inhitopes and a cyclopeptoid scaffold. This companion article details the theoretical aspects of this former study. A thermodynamic model is developed and validated, compared to literature, and extended to account for particularities of the charged DNJ inhitopes.
Abstract The first application of cyclopeptoids in asymmetric phase‐transfer catalysis was examined. A small library of nine alternating N ‐substituted‐glycine and proline hexacyclopeptoids was tested in the enantioselective alkylation of N ‐(diphenylmethylene)glycine tert ‐butyl ester. The presence of an N ‐arylmethyl side chain in the catalyst was found to be crucial for the synthesis of α‐amino acids with up to 73 % ee .
