Cyclic Octamer Peptoids: Simplified Isosters of Bioactive Fungal Cyclodepsipeptides.

Cyclic peptoids have recently emerged as an important class of bioactive scaffolds with unique conformational properties and excellent metabolic stabilities. In this paper, we describe the design and synthesis of novel cyclic octamer peptoids as simplified isosters of mycotoxin depsipeptides bassianolide, verticilide A1, PF1022A and PF1022B. We also examine their complexing abilities in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB) salt and explore their general insecticidal activity. Finally, we discuss the possible relationship between structural features of free and Na⁺-complexed cyclic octamer peptoids and bioactivities in light of conformational isomerism, a crucial factor affecting cyclic peptoids' biomimetic potentials.

Structural Basis of Outstanding Multivalent Effects in Jack Bean α-Mannosidase Inhibition.

Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic-level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high-resolution crystal structures of the Jack bean α-mannosidase (JBα-man) in apo and inhibited states. The three-dimensional structure of JBα-man in complex with the multimeric cyclopeptoid-based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition.

Comparison of Cell Permeability of Cyclic Peptoids and Linear Peptoids.

Cyclic peptoids are emerging as an attractive class of peptidomimetics. Compared to their linear counterparts, cyclic peptoids should have increased conformational rigidity and preorganized structures, enabling them to bind more tightly to target proteins without major entropy penalty. Because cyclic peptoids lack the amide protons in their backbones like linear peptoids, it is perceived that cyclic peptoids are seemingly cell permeable as much as linear peptoids. However, no systematic investigation for cell permeability of cyclic peptoids has been reported yet. Here, we, for the first time, demonstrate that cyclic peptoids are far more cell permeable than linear counterparts irrespective of their size and side chains. This study highlights that cyclic peptoids, along with combinatorial library and high-throughput screening technologies, will serve as a rich source of protein binding molecules, particularly targeting intracellular proteins, given their excellent cell permeability in addition to their conformational rigidity and proteolytic stability.

Synthesis, crystallization, X-ray structural characterization and solid-state assembly of a cyclic hexapeptoid with propargyl and methoxyethyl side chains.

The synthesis and the structural characterization of a cyclic hexapeptoid with four methoxyethyl and two propargyl side chains have disclosed the presence of a hydrate crystal form [form (I)] and an anhydrous crystal form [form (II)]. The relative amounts of form (I) and form (II) in the as-purified product were determined by Rietveld refinement and depend on the purification procedures. In crystal form (I), peptoid molecules assemble in a columnar arrangement by means of side-chain-to-backbone C=CH...OC hydrogen bonds. In the anhydrous crystal form (II), cyclopeptoid molecules form ribbons by means of backbone-to-backbone CH2...OC hydrogen bonds, thus mimicking ß-sheet secondary structures in proteins. In both crystal forms side chains act as joints among the columns or the ribbons and contribute to the stability of the whole solid-state assembly. Water molecules in the hydrate crystal form (I) bridge columns of cyclic peptoid molecules, providing a more efficient packing.

Facile solid-phase parallel synthesis of linear and cyclic peptoids for comparative studies of biological activity.

A series of linear and cyclic peptoids, which were expected to possess better pharmacokinetic properties and biological activities for blocking the interaction between apolipoprotein E and amyloid-ß, were designed and synthesized as possible therapeutic agents. Peptoids were easily synthesized on solid-phase by the submonomer strategy and polar side chain-containing amines were effectively introduced under the modified reaction conditions. For the synthesis of cyclic peptoids, ß-alanine protected with the 2-phenylisopropyl group, which could be selectively removed by 2% TFA, was used as a primary amine to afford a complete peptoid unit. The macrolactamization between the carboxylic acid of ß-alanine moiety and terminal amine of peptoids was successfully performed in the presence of the PyAOP coupling agent on solid-phase in all the cases, providing various sizes of cyclic peptoids. In particular, some cyclic peptoids prepared in this study are the largest in size among cyclic peptoids reported to date. The synthetic strategy which was adopted in this study can also provide a robust platform for solid-phase construction of cyclic peptoid libraries. Currently, synthetic peptoids have been used to test interesting biological activities including the ApoE/Aß interaction inhibition, nontoxicity, the blood-brain barrier permeability, etc.