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In this study, a new library of1,2,3-triazole arylpiperazine derivatives, possessing propylor butyl carbon chains in between arylpiperazine and 1,2,3-triazole moieties, were designed and synthesized in an effortto further understand the structure-activity relationship, andtheir binding affinities towards dopamine D

Department of Polar Sciences, University of Science and Technology, Incheon 406-840, KoreaReceived July 26, 2012, Accepted August 13, 2012Until now, few groups reported the antifreeze activity of cyclic glycopeptides; however, the tedious syntheticprocedure is not amenable to study the intensive structure activity relationship. A series of N-linked cyclicglycopeptoids and glycopeptide have been prepared to evaluate antifreeze activity as a function of peptidebackbone cyclization and methyl stereochemical effect on the rigid Thr position. This study has combined thecyclization protocol with solid phase peptide synthesis and obtained significant quantities of homogeneouscyclic glycopeptide and glycopeptoids. Analysis of antifreeze activity revealed that our cyclic peptidedemonstrated RI activity while cyclic glycopeptoids showed no RI activity. These results suggest that the subtlechanges in conformation and Thr orientation dramatically influence RI activity of N-linked glycopeptoids Key Words : Cyclic glycopeptide, Ice recrystallization inhibition, Solid phase synthesis, Cyclic glycopeptoidIntroductionAntifreeze glycoproteins (AFGPs) are essential materialsthat allow organism to thrive in harsh conditions. Fish,bacteria and other organisms produce AFGPs which havethe ability to inhibit the growth of ice, and thus allow themto survival in subzero temperature.

Department of Polar Sciences, University of Science and Technology, Incheon 406-840, KoreaReceived February 29, 2012, Accepted April 2, 2012Key Words : Antifreeze glycoproteins (AFGPs), Thermal hysteresis activity, Ice morphology, Hexagonal bi-pyramid, CarbohydrateAntifreeze glycoproteins (AFGPs) are found in the plasmaof deep sea polar fish such as the Antarctic notothenioidsand the northern cods.

One of the obvious disadvantages of natural peptides is their liability to proteases. Among the several solutions for this issue, peptoids or oligomers of N-substituted glycine have emerged as a promising tool that may enhance the stability of proteolysis-susceptible natural peptides. We have synthesized the drosocin and its glyco-peptoid analogues linked O-GalNAc at the Thr11 residue. One of our glyco-peptoid analogues showed an increased antibacterial activity by the modification of the Thr11 residue with glyco-peptoid. Structure–activity relationship studies revealed that the antibacterial activity by glyco-peptoid drosocin requires three key elements: free hydroxyl group on the carbohydrate moiety, γ-methyl group of the Thr11 residue derivative and (S)-configuration over (R)-configuration.

Antimicrobial peptides have recently gained the much attention because of their ability to make defense system from attacking bacterial infections. Drosocin has been considered as very attractive antibiotic agents because of low toxicity against human erythrocytes and active at the low concentration. We have studied the structureactivity relationship of a glycopeptide drosocin focused on the N-acetyl-D-galactoside at residue. Based on the radial diffusion assay, we found that the acetylation of carbohydrate moiety increased the antimicrobial activity and the , present in the middle of drosocin plays an important role in the antimicrobial activity. Our results provide a good lead compound for further studies on the design of drosocin-based analogues targeting glyco linked Thr site.

Stereoselective epoxidation of [4.3.3]propellane 16 set the stage for the Lewis acid catalyzed stereospecific ring contraction to an oxygenated modhephene structure and eventually led to the total synthesis of (–)-13-acetoxymodhephene and (+)-14-acetoxymodhephene. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Recent progress in the development of peptide-derived Polo-like kinase (Plk1) polo-box domain (PBD) inhibitors has led to the synthesis of multiple peptide ligands with high binding affinity and selectivity. However, few systematic analyses have been conducted to identify key Plk1 residues and characterize their interactions with potent Plk1 peptide inhibitors. We performed systematic deletion analysis using the most potent 4j peptide and studied N-terminal capping of the minimal peptide with diverse organic moieties, leading to the identification of the peptidomimetic 8 (AB-103) series with high binding affinity and selectivity. To evaluate the bioavailability of short peptidomimetic ligands, PEGylated 8 series were synthesized and incubated with HeLa cells to test for cellular uptake, antiproliferative activity, and Plk1 kinase inhibition. Finally, crystallographic studies of the Plk1 PBD in complex with peptidomimetics 8 and 22 (AB-103-5) revealed the presence of two hydrogen bond interactions responsible for their high binding affinity and selectivity.

Diversity of sequence and structure in naturally occurring antimicrobial peptides (AMPs) limits their intensive structure–activity relationship (SAR) study. In contrast, peptidomimetics have several advantages compared to naturally occurring peptide in terms of simple structure, convenient to analog synthesis, rapid elucidation of optimal physiochemical properties and low-cost synthesis. In search of short antimicrobial peptides using peptidomimetics, which provide facile access to identify the key factors involving in the destruction of pathogens through SAR study, a series of simple and short peptidomimetics consisting of multi-Lys residues and lipophilic moiety have been prepared and found to be active against several Gram-negative and Gram-positive bacteria containing methicillin-resistant Staphylococcus aureus (MRSA) without hemolytic activity. Based on the SAR studies, we found that hydrophobicity, +5 charges of multiple Lys residues, hydrocarbon tail lengths and cyclohexyl group were crucial for antimicrobial activity. Furthermore, membrane depolarization, dye leakage, inner membrane permeability and time-killing kinetics revealed that bacterial-killing mechanism of our peptidomimetics is different from the membrane-targeting AMPs (e. g. melittin and SMAP-29) and implied our peptidomimetics might kill bacteria via the intracellular-targeting mechanism as done by buforin-2.

BACKGROUND: Over the years, a great deal of effort has been focused on the design and synthesis of potent, linear peptide inhibitors targeting the polo-like kinase 1 (Plk1), which is critically involved in multiple mitotic processes and has been established as an adverse prognostic marker for tumor patients. Plk1 localizes to its intracellular anchoring sites via its polo-box domain, and inhibiting the Plk1 polo-box domain has been considered as an approach to circumvent the specificity problems associated with inhibiting the conserved adenosine triphosphate-binding pocket. The polo-box domain consists of two different binding regions, such as the unique, broader pyrrolidine-binding pocket and the conserved, narrow, Tyr-rich hydrophobic channel, among the three Plk polo-box domains (Plks 1-3), respectively. Therefore, the studies that provide insights into the binding nature of the unique, broader pyrrolidine-binding pocket might lead to the development of selective Plk1-inhibitory compounds. METHODOLOGY/PRINCIPAL FINDINGS: In an attempt to retain the monospecificity by targeting the unique, broader pyrrolidine-binding pocket, here, for the first time, a systematic approach was undertaken to examine the structure-activity relationship of N-terminal-truncated PLHSpTM derivatives, to apply a site-directed ligand approach using bulky aromatic and non-aromatic systems, and to characterize the binding nature of these analogues using X-ray crystallographic studies. We have identified a new mode of binding interactions, having improved binding affinity and retaining the Plk1 polo-box domain specificity, at the pyrrolidine-binding pocket. Furthermore, our data revealed that the pyrrolidine-binding pocket was very specific to recognize a short and bulky hydrophobic ligand like adamantane, whereas the Tyr-rich hydrophobic channel was specific with lengthy and small hydrophobic groups. CONCLUSION/SIGNIFICANCE: The progress made using our site-directed ligands validated this approach to specifically direct the ligand into the unique pyrrolidine-binding region, and it extends the applicability of the strategy for discovering selective protein-protein interaction inhibitors.

p18INK4c is a member of a family of INK4 proteins that function to arrest the G1 to S cell cycle transition by inhibiting the activity of the cyclin-dependent kinases 4 and 6. The X-ray crystal structure of the human p18INK4c protein to a resolution of 1.95 A reveals an elongated molecule comprised of five contiguous 32- or 33-residue ankyrin-like repeat units. Each ankyrin-like repeat contains a beta-strand helix-turn-helix extended strand beta-strand motif that associates with neighboring motifs through beta-sheet, and helical bundle interactions. Conserved ankyrin-like repeat residues function to facilitate the ankyrin repeat fold and the tertiary interactions between neighboring repeat units. A large percentage of residues that are conserved among INK4 proteins and that map to positions of tumor-derived p16INK4 mutations play important roles in protein stability. A subset of these residues suggest an INK4 binding surface for the cyclin-dependent kinases 4 and 6. This surface is centered around a region that shows structural features uncharacteristic of ankyrin-like repeat units.

Here we report for the first time the synthesis of Histidine (His) derived lipo-amino acids having pendant lipid tails at N(τ)- and N(π)-positions on imidazole group of His and applied it into synthesis of lipo-peptides. The attachment of His-derived lipo-amino acid into the very short inactive cationic peptides endows potent antimicrobial activity against Gram-positive and Gram-negative bacteria without hemolytic activity. Furthermore, our designed His-derived lipo-peptidomimetics (HDLPs) consisting of two or three residues displayed strong anti-MRSA activity and protease stability as well as retained potent antimicrobial activity under high salt concentration. Our results demonstrate that the novel lipo-amino acid is highly flexible to synthesize and carry out the extensive structure-activity relationship (SAR) on lipo-antimicrobial peptidomimetics and represents a unique amenable platform for modifying parameters important for antimicrobial activity. Through this study, we proved that the discovery of His-derived lipo-amino acid and the corresponding HDLPs are an excellent candidate as a lead compound for the development of novel antimicrobial agents.

Since the bacterial resistance to antibiotics is increasing rapidly, numerous studies have contributed to the design and synthesis of potent synthetic mimics of antimicrobial peptides (AMPs). In an attempt to find the pharmacophore of short antimicrobial peptidomimetics through systematic tuning of hydrophobic and hydrophilic patterns, we have identified a set of short histidine-derived antimicrobial peptides (SAMPs) with potent and broad-spectrum activity. A combination of high antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), without hemolytic activity and proteolytic stability makes these molecules promising candidates for novel antimicrobial therapeutics.

The polo-box domain (PBD) of polo-like kinase 1 (Plk1) is essentially required for the function of Plk1 in cell proliferation. The availability of the phosphopeptide-binding pocket on PBD provides a unique opportunity to develop novel protein–protein interaction inhibitors. Recent identification of a minimal 5-residue-long phosphopeptide, PLHSpT, as a Plk1 PBD-specific ligand has led to the development of several peptide-based inhibitors, but none of them is cyclic peptide. Through the combination of single-peptoid mimics and thio-ether bridged cyclization, we successfully demonstrated for the first time two cyclic peptomers, PL-116 and PL-120, dramatically improved the binding affinity without losing mono-specificity against Plk1 PBD in comparison with the linear parental peptide, PLHSpT. These cyclic peptomers could serve as promising templates for future drug designs to inhibit Plk1 PBD.

Department of Polar Sciences, University of Science and Technology, Incheon 406-840, KoreaReceived August 20, 2012, Accepted September 12, 2012Key Words : Glycopeptoid, Ice recrystallization inhibition, Positional scanningAntifreeze glycoproteins (AFGPs) bind to the ice crystals,thereby inhibit ice crystal growth. The discovery of AFGPsin the blood serum of fish by De Vries demonstrated thatAFGPs is an essential biomaterial for fish to survive at sub-zero temperature in the Antarctic Sea.