Day 1 :
Keynote Forum
Tatsuya Takagi
Osaka University, Japan
Keynote: SBDD of MDM2 inhibitors using FMO and data mining method
Time : 09:45- 10:25
Biography:
Abstract:
Keynote Forum
Victor J. Hruby
University of Arizona, USA
Keynote: Design of novel receptor selective bioavailable peptide and peptidomimetic ligands for G protein coupled receptors involved in major degenerative diseases
Time : 10:25-11:05
Biography:
Abstract:
G-Protein Coupled Receptors (GPCRs) are targets for 30% of current drugs, but there are many unmet needs because these receptors and their ligands are intimately involved in many of our degenerative diseases. It has been difficult to obtain drugs that are effective and without side effects because there often are multiple subtypes of receptors and the endogenous hormones and neurotransmitters are non-selective. The 5 melanocortin receptors (MCRs) and the 3 opiate receptors (ORs) are important examples that are involved in many degenerative diseases, both central and peripheral. There is only 1 drug on the market for the MCRs, and the drugs on the market for the ORs are toxic and currently a great concern because of the drug overdose epidemic, which is costing billions and thousands of lives. To address this problem, we have developed a multimodal approach, using a combination of novel peptide and peptidomimetic scaffolds that address drug design in 3-dimensional space, with novel cyclic templates, computer assisted ligand/receptor interactions, orthosteric and allosteric agonist and antagonist activities, receptor selectivity and bioavailability for both the blood brain barrier and oral/transdermal availability. As time permits, we will illustrate this approach with design of melanotropin ligands that are highly selective agonists or antagonists for only 1 of the melanocortin receptors involved in pigmentary disorders, cancer, feeding and sexual disorders and neurodegeneration. For the opiate receptors, multivalent ligands that target opiate receptors and other receptors involved in pain pathways all in single ligands which do not have the toxicities of current opiates.
Keynote Forum
Jaein Ha
Korea University College of Medicine
Keynote: The Anticancer effect of a specific Myokine, Vimentin
Time : 10:50-11:30
Biography:
Jaein Ha is an Undergraduate student at Korea University College of Medicine. She has studied Organic Chemistry and is interested in the fields such as Bioorganic Chemistry and Pharmacology. Now, she is doing a research under her academic advisor, Kim, Hyeon Soo (Anatomy Department, Korea University College of Medicine). Her research interest is myokine, which is a molecule secreted from muscle cells. She tries to identify specific myokine which are associated with cell metabolism
Abstract:
Myokines are known to suppress some kinds of tumor. This fact makes it possible to explain the correlation between physical activities and cancer. The researcher suggests that Vimentin, an intermediate filament, is a novel myokine and has an anticancer effect on pancreatic cancer. Vimentin was shown to be secreted from muscle cells by muscle contraction. Furthermore, Vimentin treatment on L6 cell increased phosphorylation of AMPK and ACC. These results imply that Vimentin is associated with signaling pathways regulating various metabolisms. MTT assay results demonstrated that Vimentin controls the viability of pancreatic cancer cell, MIA-Pa-Ca-2. The study provides considerable insight into role of Vimentin as a myokine. Muscle contraction leads to secretion and Vimentin is involved in metabolism related to cancer. The evidence from this study also suggests that Vimentin could be used as a drug for cancer treatment. This study is the first step of developing a useful drug for cancer.
- Drug Chemistry | Medicinal Chemistry and Drug Discovery | Cancer Studies |Biochemistry | Targeted Drug Delivery System | New Trends in Pharmacology & Drug Development | Computer Aided Drug Designing-CADD
Location: Dallas , USA
Session Introduction
Jaein Ha
Korea University College of Medicine, Korea
Title: The Anticancer effect of a specific Myokine, Vimentin
Biography:
Abstract:
Myokines are known to suppress some kinds of tumor. This fact makes it possible to explain the correlation between physical activities and cancer. The researcher suggests that Vimentin, an intermediate filament, is a novel myokine and has an anticancer effect on pancreatic cancer. Vimentin was shown to be secreted from muscle cells by muscle contraction. Furthermore, Vimentin treatment on L6 cell increased phosphorylation of AMPK and ACC. These results imply that Vimentin is associated with signaling pathways regulating various metabolisms. MTT assay results demonstrated that Vimentin controls the viability of pancreatic cancer cell, MIA-Pa-Ca-2. The study provides considerable insight into role of Vimentin as a myokine. Muscle contraction leads to secretion and Vimentin is involved in metabolism related to cancer. The evidence from this study also suggests that Vimentin could be used as a drug for cancer treatment. This study is the first step of developing a useful drug for cancer.
Hongli Wu,
University of North Texas Health Science Center, USA
Title: Ocular drug discovery: New targets and mechanisms for age-related macular degeneration
Biography:
Hongli Wu has completed her PhD from Peking University and Postdoctoral studies from the University of Nebraska-Lincoln. She is the Assistant of Pharmaceutical Sciences at the University of North Texas Health Science Center. She has published more than 25 papers in reputable journals
Abstract:
Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. The lack of adequate AMD animal models and poorly understood pathogenesis have greatly hindered our progress in therapeutic development. To address these shortcomings, this project was designed to examine how retinal redox dysregulation leads to AMD and characterize glutaredoxin 2 (Grx2), a mitochondrial thiol redox regulating enzyme, knockout mice as a new animal model for AMD. We found that Grx2 KO mice developed age-dependent retinal degenerative pathology. By 12-month of age, Grx2 null mice showed ~50% decrease in a-wave and ~30% decline in b-wave amplitude (n=8, P<0.01). Histological analysis revealed extensive RPE lesions, including RPE atrophy, vacuolation, hyper- and hypo-pigmentation, sub-RPE deposits, and loss of tight junction integrity. Age-dependent lipofuscin accumulation was also observed in Grx2 KO mice. Furthermore, Grx2 KO mice demonstrated increased marker of mitochondrial oxidative damage including PSSG accumulation. In conclusion, Grx2 plays a critical role in maintaining the mitochondrial redox homeostasis in the aging retina. Grx2 deficiency causes PSSG accumulation and sensitizes RPE cells to age-related oxidative damage, leading to RPE degeneration and photoreceptor damage. As a new animal model for AMD, Grx2 KO mice will provide new insights into pathogenesis and therapeutics of AMD. Grx2 may serve as a new therapeutic target for AMD and the Grx2 activating drugs may be used to treat AMD.
Jung-Mo Ahn
University of Texas at Dallas, USA
Title: Crafting Alpha-helix mimetics for targeting protein-protein interactions
Biography:
Jung-Mo Ahn has received his PhD in Chemistry from the University of Arizona and completed his Postdoctoral studies in the Scripps Research Institute. He is Associate Professor in Chemistry at the University of Texas at Dallas and a Council Member of the American Peptide Society. His research mainly focuses on structure-based design of peptidomimetics targeting protein-protein interactions.
Abstract:
Protein-protein interactions are one of the fundamental processes that regulate numerous key cellular pathways. Since α-helical structures are frequently found on the interfaces of protein complexes, short helical peptides derived from such proteins have been considered as a valuable tool for research and clinical applications. However, peptides in general may suffer from drawbacks that can severely compromise their effective in vivo use, such as rapid enzymatic degradation, poor bioavailability, and lack of membrane permeability. Thus, small molecules that mimic functions of helical peptides would be of great interest in targeting and disrupting protein-protein interactions that take place inside cells. To the end, we have designed oligo-benzamides as versatile scaffolds to emulate protein helical surfaces. The rigid oligo-benzamide scaffolds can present multiple functional groups corresponding to the side chains found on one helical face. In addition to the outstanding α-helix mimicry, oligo-benzamides can be efficiently synthesized by following high-yielding and iterative steps in solution- and solid-phase. Nuclear receptors like androgen receptor and estrogen receptor recruit a variety of coactivator proteins to exert their functions, and many of the molecular recognition are triggered by consensus LXXLL motifs. We have designed oligobenzamides based on the sequence and structure of the helical LXXLL motifs, and they demonstrated utilities in disrupting NR-coactivator protein complex formation, inhibiting NR-mediated gene transcription, and blocking NR-mediated cell proliferation in prostate and breast cancer cell lines. These exciting results indicate that oligo-benzamides are effective tools to mimic functions of α-helices and may have a high potential in biomedical research.