• Bulletin of the Korean Chemical Society
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• v.23 no.10
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• pp.1481-1489
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• 2002

• Toxicological Research
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• v.29 no.1
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• pp.21-25
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• 2013

The selective targeting of an integrin ${\alpha}_v{\beta}_3$ receptor using radioligands may enable the assessment of angiogenesis and integrin ${\alpha}_v{\beta}_3$ receptor status in tumors. The aim of this research was to label a peptidomimetic integrin ${\alpha}_v{\beta}_3$ antagonist (PIA) with $^{99m}Tc(CO)_3$ and to test its receptor targeting properties in nude mice bearing receptor-positive tumors. PIA was reacted with tris-succinimidyl aminotriacetate (TSAT) (20 mM) as a PIA per TSAT. The product, PIA-aminodiacetic acid (ADA), was radiolabeled with $[^{99m}Tc(CO)_3(H_2O)_3]^{+1}$, and purified sequentially on a Sep-Pak C-18 cartridge followed by a Sep-Pak QMA anion exchange cartridge. Using gradient C-18 reverse-phase HPLC, the radiochemical purity of $^{99m}Tc(CO)_3$-ADA-PIA (retention time, 10.5 min) was confirmed to be > 95%. Biodistribution analysis was performed in nude mice (n = 5 per time point) bearing receptor-positive M21 human melanoma xenografts. The mice were administered $^{99m}Tc(CO)_3$-ADA-PIA intravenously. The animals were euthanized at 0.33, 1, and 2 hr after injection for the biodistribution study. A separate group of mice were also co-injected with 200 ${\mu}g$ of PIA and euthanized at 1 hr to quantify tumor uptake. $^{99m}Tc(CO)_3$-ADA-PIA was stable in phosphate buffer for 21 hr, but at 3 and 6 hr, 7.9 and 11.5% of the radioactivity was lost as histidine, respectively. In tumor bearing mice, $^{99m}Tc(CO)_3$-ADA-PIA accumulated rapidly in a receptor-positive tumor with a peak uptake at 20 min, and rapid clearance from blood occurring primarily through the hepatobiliary system. At 20 min, the tumor-to-blood ratio was 1.8. At 1 hr, the tumor uptake was 0.47% injected dose (ID)/g, but decreased to 0.12% ID/g when co-injected with an excess amount of PIA, indicating that accumulation was receptor mediated. These results demonstrate successful $^{99m}TC$ labeling of a peptidomimetic integrin antagonist that accumulated in a tumor via receptor-specific binding. However, tumor uptake was very low because of low blood concentrations that likely resulted from rapid uptake of the agent into the hepatobiliary system. This study suggests that for $^{99m}Tc(CO)_3$-ADA-PIA to be useful as a tumor detection agent, it will be necessary to improve receptor binding affinity and increase the hydrophilicity of the product to minimize rapid hepatobiliary uptake.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.175.2-175.2
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• 2003

Inhibition of the protein-modifying enzyme farnesyltransferase is considered as a major emerging strategy in cancer therapy because of the involvement of farnesylated proteins in oncogensis. We studied the structure-activity relationship of a novel class of CAAX-peptidomimetic farnesyltransferase inhibitors based on the benzophenone scaffold. FlexX docking of inhibitors confirmed reasonable fit of the molecule into the peptide binding site of farnesyltransferase. We also performed a virtual screening with LeadQuest chemical library databases to idenfity novel inhibitors of farnesyltransferase. (omitted)

• Proceedings of the SCSK Conference
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• 2003.09a
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• pp.161-161
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• 2003

The cutaneous network of unmyelinated nerve fibers is extremely dense, and closely interacts with the many cell types present in dermis and epidermis, including keratinocytes, fibroblasts, Langerhans cells, and melanocytes. Cell communication involves various neuroendocrine factors, with cell differentiating and proliferative activities, or inflammatory properties. Thus, nervous cells in the skin not only create a sensory system connected to the central nervous system, but also mediate many of the biological activities of the skin.(omitted)

• BMB Reports
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• v.36 no.6
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• pp.552-557
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• 2003

Oligomers with $\alpha$-aminooxy acids are reported to form very stable turn and helix structures, and they are supposed to be useful peptidomimetics for drug design. A recent report suggested that homochiral oxa-peptides form a strong eight-member-ring structure by a hydrogen bond between adjacent aminooxy-acid residues in a $CDCl_3$ solution. In order to design an $\alpha$-MSH analog with a stable turn conformation, we synthesized four tetramers and one pentamer, based on $\alpha$-MSH sequence, and determined the solution structures of the molecules by two-dimensional NMR spectroscopy and simulated annealing calculations. The solution conformations of the three peptidomimetic molecules (TLV, TDV, and TLL) in DMSO-$d_6$ contain a stable 7-membered-ring structure that is similar to a $\gamma$-turn in normal peptides. Newly-designed tetramer TDF and pentamer PDF have a ball-type rigid structure that is induced by strong hydrogen bonds between adjacent amide protons and carbonyl oxygens. In conclusion, the aminooxy acids, easily prepared from natural or unnatural amino acids, can be employed to prepare peptidomimetic analogues with well-defined turn structures for pharmaceutical interest.

• Bulletin of the Korean Chemical Society
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• v.27 no.9
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• pp.1371-1376
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• 2006

BACE 1 ($\beta$-secretase), a membrane bound aspartic protease, is a key enzyme in the process of amyloid precursor protein (APP) into A$\beta$ peptide which is considered to play a causative role in Alzheimers Disease (AD). Here, we reported the synthesis and inhibitory activity of optically active 3-amino-4-aryl-piperidines.

• Bulletin of the Korean Chemical Society
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• v.32 no.4
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• pp.1249-1252
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• 2011

Inhibition of BACE 1 activity is considered as a promising therapeutic target for Alzheimer's Disease (AD). Synthesis and inhibitory activities of (4-arylpiperazinyl)piperidines by bioisosteric replacement of a biaryl group with an arylpiperazine as BACE 1 inhibitors are described. The resulting (4-arylpiperazinyl)piperidines represent novel nonpeptide BACE 1 inhibitors with improved in vitro potency.

• Bulletin of Food Technology
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• v.15 no.2
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• pp.3-24
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• 2002

펩타이드와 단백질은 전사, 번역, 후번역 단계에 걸친 모든 생물학적 반응을 조절한다. 그러나 분자수준에서 구조와 기능에 대한 우리의 이해는 초보적인 수준이다. 구조와 기능의 연관성에 대한 문제는 펩타이드와 단백질 자체에 대한 것과는 좀 다르다는 것을 명확히 할 필요가 있다. Multidomain을 갖는 단백질은 작고 통합적이며, 구조적으로 제한된 부분으로 쪼개는 것은 천연 단백질의 활성을 모방하여 저분자의 nonpeptide를 설계하는데 있어서 주요한 일이다. 결정적인 역할을 수행하는 domain을 모방하는 것은 특이성과 치료 효과에 있어서 자연적으로 얻어지는 단백질 물질과 비교하여 이로운 특성을 갖을 수 있고 분자 인지 분야에 관한 연구에 유용한 단서를 제공한다(Chen etal., 1992). 한편 펩타이드는 환경에 의해 구조가 심하게 영향을 받아 특성이 쉽게 변한다(Marshall et al., 1978). 수용액 내에서 이러한 구조적 유동성 때문에 그들이 결합할 수용체나 생리활성을 띄는 구조를 결정하는 것은 어렵고 복잡한 일이다(Fauchre,1987; Hruby, 1987). 구조를 한정하면 이러한 결정을 매우 쉽게 할 수 있다(Hrubyet al., 1987). 단백질 모방학은 분자지각 연구에 강력한 수단이며, 복잡한 단백질과 펩타이드의 구조-기능관계를 탐구하고 분석하는데 독특한 방법이다. 이 장에서는 매우넓고 빠르게 확장되고 있는 Peptidomimetic연구를 간략히 소개하고 있다. 단 본문은 기술 범위를 N-Methylated 아미노산과 스테로이드 등으로 제한하여 소개한다.

• YAKHAK HOEJI
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• v.52 no.6
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• pp.466-470
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• 2008

Human cytomegalovirus expresses an unusual protein kinase UL97, a member of ${H_V}{U_L}$ family of protein kinase. UL97 can phosphorylate nucleoside analogs such as ganciclovir as well as protein/peptide. It has previously been reported that UL97 is able to phosphorylate a KESYSVYVYKV peptide and that P+5 position (K) is important. We examined the extent of contribution of other positions (P-4 through P+6) of the peptide to be substrate of UL97 using alanine substituted peptides (Ala scanning) and deleted peptides. The result suggested that the E (P-2) is negative effect and P+5 (K) is still important. The peptide YSVYVYK is the shortest substrate enough to show high activity, which could be a starting point to develop peptidomimetic drug. This study would give important information to deeply understand the substrate specificity of UL97 and develop an antiviral drug using the small peptide identified here.

• Bulletin of the Korean Chemical Society
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• v.32 no.6
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• pp.2032-2038
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• 2011

Matrix metalloproteinases (MMPs), a family of zinc-containing endopeptidases, participate in many normal processes such as embryonic development and wound repair, and in many pathological situations such as cancer, atherosclerosis, and arthritis. Peptidomimetic MMP inhibitors were designed and synthesized with N-formylhydroxylamine (retrohydroxamate) as a zinc-binding group and various side chains on the ${\alpha}$, P1', and P2' positions. Using in vitro MMP assays with purified MMPs (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-14) and fluorogenic peptide substrates, it was found that compounds 2d and 2g selectively inhibit gelatinases (MMP-2 and MMP-9) and interstitial collagenase (MMP-1). They also inhibited the chemo-invasion of fibrosarcoma HT-1080 cells and tube formation of human umbilical vascular endothelial cells in a dose-dependent manner. Our results suggest that retrohydroxamate-based MMP inhibitors, especially compounds 2d and 2g, have the potential to be used as therapeutic drugs for cancer and other MMP-related diseases.