Day 2 :
Keynote Forum
Emil Toma
University of Montreal, Canada
Keynote: Wolbachia: The fascinating, feminizing bacteria, new therapeutic and preventive avenues for filarial and some arthropod-borne infections
Time : 10:00 - 11:00
Biography:
Emil Toma has completed his DSc in Microbiology and specialization in infectious diseases in 1971, at the University of Bucharest, Romania. In 1986, he joined the University of Montreal, Canada where he is a full Clinical Professor in the Department of Microbiology, Immunology and Infectious Diseases. He has published more than 138 papers in peer-reviewed journals, 5 books and wrote several chapters in 8 other books. He also developed a “boosted-reverse transcriptase inhibitor†(patented in USA, Australia and Canada).
Abstract:
Wolbachia is an alpha-proteobacteria firstly described in 1924 by Hertig and Wolbac. It has a rickettsia-like microorganism in Culex mosquito. It was designated in 1936 by Hertig as Wolbachia pipientis, a new species. Sequence analysis of 16sRNA showed that this microorganism is related to Erlichia and Anaplasma. Wolbachia is a heritable bacterial endosymbiot utilizing the host reproductive system for its survival and dissemination. It is the intracellular parasite, the most widely spread in the animal world, infecting more than 90% of filarial nematodes and 40-70% of arthropods. In Filaria, an obligate nutritional mutualism, the most sophisticated form of symbiosis, was established during million years of evolution. Wolbachia and its surface proteins are implicated in the pathogenesis of filarial diseases and in the host immune response. The treatment of Wolbachia with tetracyclines is macro and microfilaricidal and is superior to antiparasitic therapies. In insects, there is a facultative symbiosis. Wolbachia enhances the resistance of insects (Aedes, Culex, Anopheles, Glossina) to viral or parasitic infections and diminishes sometimes the vectorial competence and infection transmission. Important basic and field research support the use of Wolbachia as an “environmentally –friendly†approach in the fight against vector-borne diseases such as Dengue, Chikungunya, West Nile fever, malaria.There is increasing world-wide interest and experience with Wolbachia in the treatment of filariasis and for the prevention of vector-borne diseases.
- Workshop Session
Location: Melia Meeting
Chair
Isabel Portero Sanchez
Complutense University, Spain
Session Introduction
Isabel Portero Sanchez
Complutense University School of Medicine, Spain
Title: Drug discovery through traditional medicines
Biography:
Isabel Portero received her MD at University of Salamanca, PhD at University of La Coruña and completed a medical specialization in Internal Medicine & Infectious diseases at “Marques de Valdecilla†University Hospital, Santander, Spain. She has dedicated her career to developing new medicinal products. She has 15 years of experience in the scientific and medical design of experiments and clinical trials for new drugs and biomarkers. She has worked as Medical Director at several Biotech companies and is also a Professor at the Department of Medicine (Universidad Complutense, Madrid). She leads a scientific group in Advanced Therapies.
Abstract:
The history of the discovery of new medicinal products have been “monopolized†by chemical agents for centuries, which it is to be said, they have offered the vast majority of important contributions to Medicine. For this reason, drug development has always been an issue of chemists and chemical engineers. Still, traditional “small drugs†(chemicals) are the most numerous and useful medical treatments we currently use to deal with many diseases. In the 80´s a new player entered that has revolutionized the treatment of many diseases: Molecular antibodies produced in living organisms factories. There medicines are classified into the term “Biotechnological drugsâ€. There is no doubt of the enormous contribution of biotechnological drugs to cancer or immune diseases clinical management. Lately, in the past 15 years, a new paradigm in drug development has been broken. Now it is not only molecules that can cure, but the cells themselves acting as medicinal products. In addition, the old idea of using genes to cure diseases, replacing wrong copies or inserting those that lack, has experienced a huge growth and development. As a result, we were ready for a new drug development scenario in which cells and genes are medicines, being called “Advanced Therapies†by EMA and FDA. Advanced Therapies drug development has a unique regulation, different from chemical and classical biotech products. Not only is the law differently, but also the processes themselves vary. Allogeneic v’s autologous source, manufacturing in cell factories, preclinical studies in which (for example) ADME does not apply, clinical studies designed differently from traditional Phase I-III trials. All these aspects and challenges foreseen for the upcoming future will be discussed in deep in this workshop.
Biography:
Dirk Büscher received his PhD in Biology in the area of Immunology from the University of Hannover, Germany, and focused his postdoctoral work at the Salk Institute, La Jolla, California, on molecular developmental biology and stem cell research. In 2004, he joined Cellerix SL and moved up to the position of Vice President of R&D representing the company in several scientific advices at EMA. Additionally he served as industry expert on mesenchymal stem cells in internal EMA workshops. In 2007 he obtained an International Executive MBA from the Instituto de Empresa (IE). 2010 He accepted a position as chief executive officer of Gri-Cel SA, a newly created fully owned subsidiary of Grifols SA, dedicated to advanced therapies and innovative therapeutic approaches. He currently serves on the boards of VCN Bioscience, Araclon Biotech, and TiGenix NV.
Abstract:
Gene Therapy approaches to fight cancer has seen promising results within the last few years, utilizing different strategies. A rather old approach is the use of oncolytic viruses (Virotherapy). Virotherapy started at the beginning of the twentieth century after the occasional observation of transient clinical remission during viral infections in cancer patients. In an initial phase almost every newly-discovered virus was injected into tumors. Later, during the 1950s and 60s, only viruses displaying natural tumor tropism were selected. Lack of clear clinical results led to virotherapy being abandoned; however increased knowledge in virology has prompted a more rational use of specially-designed viruses and a revival of this technology. Oncolytic adenoviruses are promising anticancer agents due to their ability to recognize tumor cells, infecting both dividing and non-dividing cells and selectively self-amplify inn tumor cells. After an initial infection and viral replication cancer cells are lysed and virus progeny is released, resulting in an infection of neighboring cancer cells. Theoretically infection and replication can continue until the whole tumor mass is eradicated. However the stromal structure often limits an effective spreading. Virus may also reach distant metastases by entering the blood stream. Another limitation for the spreading and body-wide distribution is the pre-existing/induced immune response against an oncolytic virus. We currently test in phase I clinical trials an oncolytic adenovirus expressing a stromal degrading enzyme, which will hopefully shed more light on its usefulness and /or limitations.
Rossana GarcÃa
Gradocell, Spain
Title: Production of advanced therapy products: Scale up to industry processes?
Biography:
Rossana GarcÃa studied Biological Sciences at the Complutense University of Madrid (Spain) and is Master in Production and Applied Quality. She has more than 28 years experience in pharmaceutical industry and research, working for 10 years as Research Technician in Antibióticos-Farma SA, where she was responsible for the cell culture laboratory. Later, she specialized in the cultivation of stem cells at the National Center for Biotechnology (National Research Council), where she worked for 3 years in the laboratory of Dr. Antonio Bernad, specialist in this field. After this specialization, she joined Genetrix Group at the Department of Cell Therapy where she worked for 4 years in R&D. Finally, she worked for 6 years as Manufacturing Manager in the Manufacturing Plant of Cell Based Medicinal Products (CBMPs) of Cellerix SA (Genetrix Group company) actually Tigenix. She is Founder, CEO and Technical Consultant of Gradocell Group (Gradocell Consulting and Gradocell Pharma SL) since 2010.
Abstract:
Development of advanced therapies medicinal products represent a major challenge for companies or institutions who choose to manufacture and promote this type of medicines. ATMPs production requires a deep understanding of GMP, as well as a strong technical qualification. Facilities and equipment are unusual compared to the manufacture of conventional drugs, which increases the manufacturing complexity. From the viewpoint of quality control, analysis techniques are not very robust and some of them very complex. However, these medicines have become in the last 10 years in a hopeful alternative for some incurable diseases. This has led to extensive development of medicinal products for Gene and Cell Therapy for many indications, having conducted numerous clinical trials with these therapies. Currently, most of these therapies are experimental, with good safety and promising signs of efficacy. Only four products are approved by regulatory agencies and marketing stage, although it is estimated that in the coming years to increase the number of registrations of new ATMPs.
- Chemotherapy side effects and precaution
Location: Room 1
Session Introduction
Hiroyuki Osada
RIKEN Center for Sustainable Resource Science, Japan
Title: Screening of novel antimalarial agents in RIKEN NPDepo
Biography:
Hiroyuki Osada is a Deputy Director of RIKEN Center for Sustainable Resource Science. He completed his education from The University of Tokyo in Department of Agricultural Chemistry. He is editorial member of different journals. He also published more than 9 research papers.
Abstract:
Malaria is one of the most serious infectious diseases. Since parasite strains resistant to traditional antimalarial drugs such as chloroquine (CLQ) and artemisinin (ART) derivatives appeared, novel antimalarial agents are required to be developed urgently. I will introduce the screening method and the hit compounds showing the antimalarial activity in this presentation. It is known that malaria parasite has high LDH activity. We established a HTS system using the LDH assay to isolate growth inhibitors of the parasite strain 3D7 cultured in vitro. Using this system, we selected 450 compounds from 17,000 compounds of RIKEN NPDepo (Natural Products Depository) chemical library with 5 µg/mL or less IC90 activity of parasite growth. As the second screening, we evaluated the toxicity toward mouse NIH3T3 and rat NRK cells of these compounds. Eighty six compounds showed selective inhibition against parasite with IC50 values lower than one thirtieth of those toward mammalian cells. Finally, as the third screening, we examined growth inhibitory effect of these 86 compounds on the CLQ resistant parasite strains (K1 and Dd2) and found that 36 compounds were as effective on the resistant strains as on 3D7 strain. NPD10928 (IC50 88 nM) was selected as one of the potent inhibitors against malaria parasites. We administrated NPD10928 to a malaria infectious mouse (ip, 20 mg/kg), and found that the growth of parasite was reduced significantly. In addition, I will introduce other antimalarial agents that were found by our screening.
Minoru Yoshida
RIKEN Center for Sustainable Resource Science, Japan
Title: Chemical genomics for target identification of antifungal theonellamides
Biography:
Identification of the cellular targets of bioactive small molecules is a major challenge in the development of these molecules as biological tools and therapeutics. Recently, much attention has been drawn to a chemical genetic approach, which uses physical and/or genetic interaction between the compound and its target. Thanks to a wealth of genomic information, genome-wide screening of genetic interaction has become available. We constructed a whole ORF library (ORFeome) of fission yeast and performed reverse proteomics including global analyses of protein subcellular localization (localizome) and protein gel mobility (mobilitome). In combination with these databases and chemical genetic profiling using the strains expressing the ORFeome, we developed a systematic method for drug target identification. This method enabled us to identify the rather unusual mechanism of action of theonellamides (TNMs), marine antifungal cyclic peptides. TNMs were shown to bind to 3beta-hydroxysterols including ergosterol in the fungal cell membrane, thereby inducing abnormal accumulation of 1,3-ï¢-glucan, proving the effectiveness of chemical genomics. Furthermore, we show that in mammalian cells TNMs recognize specific cholesterol-containing membrane domains, induce phase separation of lipid membranes, and induce cell contraction. The usefulness of TNMs as a tool for lipid biology will be discussed.
Abstract:
Identification of the cellular targets of bioactive small molecules is a major challenge in the development of these molecules as biological tools and therapeutics. Recently, much attention has been drawn to a chemical genetic approach, which uses physical and/or genetic interaction between the compound and its target. Thanks to a wealth of genomic information, genome-wide screening of genetic interaction has become available. We constructed a whole ORF library (ORFeome) of fission yeast and performed reverse proteomics including global analyses of protein subcellular localization (localizome) and protein gel mobility (mobilitome). In combination with these databases and chemical genetic profiling using the strains expressing the ORFeome, we developed a systematic method for drug target identification. This method enabled us to identify the rather unusual mechanism of action of theonellamides (TNMs), marine antifungal cyclic peptides. TNMs were shown to bind to 3beta-hydroxysterols including ergosterol in the fungal cell membrane, thereby inducing abnormal accumulation of 1,3-ï¢-glucan, proving the effectiveness of chemical genomics. Furthermore, we show that in mammalian cells TNMs recognize specific cholesterol-containing membrane domains, induce phase separation of lipid membranes, and induce cell contraction. The usefulness of TNMs as a tool for lipid biology will be discussed.
Emil Toma
University of Montreal, Canada
Title: Clindamycin & primaquine for Pneumocystis jirovecii pneumonia; 27 years after
Biography:
Emil Toma has completed his DSc in Microbiology and specialization in infectious diseases in 1971, at the University of Bucharest, Romania. In 1986, he joined the University of Montreal, Canada where he is a full Clinical Professor in the Department of Microbiology, Immunology and Infectious Diseases. He has published more than 138 papers in peer-reviewed journals, 5 books and wrote several chapters in 8 other books. He also developed a “boosted-reverse transcriptase inhibitor†(patented in USA, Australia and Canada).
Abstract:
Pneumocystis jirovecii pneumonia (PCjP) is still a common AIDS-defining disease and cause of mortality in HIV-infected persons. Moreover, it is increasingly reported in other immunodeficient populations. Conventional treatments, trimethoprim-sulfamethoxazole (Tmp/Smx), pentamidine or atovaquone are effective in 80-96% of cases and/or carry a high risk of drug-related events. Increasing prevalence of sulpha allergy or intolerance is now reported. The combination of clindamycin with primaquine (Cm/Prq) is known for its anti PCjP effects since 1988, in addition to their effects on Plasmodium infections. Our group firstly reported its use in humans as salvage therapy in patients unresponsive or intolerant to conventional agents in 1988. A meta-analysis of salvage therapy for PCjP who failed a first regimen reported that Cm/Prq was the most effective alternative therapy. We also performed two double-blinded controlled studies (1993, 1998) showing that Cm/Prq is as effective and better tolerated (P=0.04) than Tmp/Smx when used as primary therapy. Our results were confirmed by larger studies and 2 other meta-analysis showing that Cm/Prq had the same rates of success, failure or treatment-limiting effects as Tmp/Smx or Tmp/dapsone. Atovaquone was less effective than Tmp/Smx, had higher relapse rates and it is much more expensive. In conclusion, Cm/Prq is a reasonable alternative to Tmp/Smx for both salvage and primary therapy of PCjP in both HIV-infected or other immunodeficient populations and this after 27 years in use.
Natalia Martins
1Polytechnic Institute of Braganca, Portugal
Title: The use of different phenolic compounds rich extracts obtained from cultivated thyme for antioxidant and antibacterial purposes
Biography:
Natalia Martins is a PhD student from University of Minho since March 2013. She graduated in Dietetics and Nutrition from Polytechnic Institute of Bragança (including a period of extra-curricular training in Brazil), in Natural Medicine from School of Alternative and Complementary Medicines of Oporto, and also attended other short courses in Traditional Medicine. She has published 4 articles in ISI and Scopus indexed journals, and presented 10 abstracts in national and international conferences/congresses.
Abstract:
Currently, oxidative stress related damages and opportunistic infections exert a direct implication on public health. Environmental factors and whole cellular metabolism comprises the first intervenient on the imbalance homeostasis. Additionally, stress and the overuse of chemical substances, namely antimicrobial drugs, improve this problem by two ways: Increasing free radicals generation and suppressing immune system functions. Thus, to improve health and wellbeing other safer and effective alternatives are necessary. Thymus vulgaris L. (thyme) has been widely cultivated not only for nutritional but also medicinal purposes. Essential oils have been the main focus of research studies but its incorrect use might provide toxicity. In the present study, the antioxidant and antibacterial activities of thyme phenolic-compounds rich extracts, obtained by decoction, infusion and hydroalcoholic extraction were analyzed and compared. Furthermore, the extracts were characterized in terms of phenolic compounds by HPLC-DAD/ESI-MS. The extract obtained by decoction evidenced the most pronounced antioxidant (reducing power, free radicals scavenging activity and lipid peroxidation inhibition) and antibacterial (against gram-positive and gram-negative bacteria) potential, related to the its highest abundance of phenolic compounds, followed by the extracts obtained by infusion and hydroalcoholic extraction, respectively. Rosmarinic acid (in all the preparations), luteolin 7-O-glucoside (in the hydroalcoholic extract) and luteolin 7-O-glucuronide (in the infusion and decoction) were the most abundant phenolic acids and flavonoids found. The obtained data supports the idea that the compounds responsible for the antioxidant and antibacterial activities are water-soluble, conferring considerable health benefits to the studied plant that could be included as complement of daily food.
Qin-Shu Shao
University of Minnesota, USA
Title: Tentative application of middle gastrectomy in early gastric cancer in the middle one-third of the stomach
Biography:
Qin-Shu Shao is a Surgery Professor, Chief Physician and Director of Gastrointestinal Surgery of Zhejiang Provincial People's Hospital. He has published more than fifty articles in important national journals, 8 articles in SCI. He is a Standing Committee of Zhejiang Provincial Surgery Branch of Chinese Medical Association, a member of the National gastric Professional Committee of Chinese Anti-Cancer Association, a Professional Committee of hepatobiliary and pancreatic tumors surgery of Zhejiang Province, a Magazine Editorial of “Chinese Journal of Gastrointestinal Surgery" and "Chinese Journal of Digestive Surgery".
Abstract:
This lecture will address a variety of topics related to the use of middle gastrectomy with regional lymph node resection as a new therapeutics in early gastric cancer in the middle one-third of the stomach. And will include discussion of: The therapeutics for gastric cancer in recent years; compare the advantage and disadvantage of these therapeutics; compare the difference of surgery time, lymph node resection, aerating time, hospitalization time post operation, feed after 3 months and Visick graded index between group A (middle gastrectomy with regional lymph node resection), group B (total gastrectomy with D1 lymph node resection) and group C (endoscopic mucosal resection.). We found that middle gastrectomy with regional lymph node resection in early gastric cancer will not increase the risk and time of surgery and it can reduce the risk of lymph node migrating, complication related to surgery and improve the quality of life.
Biography:
Triple-negative breast cancer (TNBC) is a high risk form of this disease, even after surgery, due to the absence of targets for hormone treatment and anti-Her-2 therapy. Chemotherapy is the main therapeutic strategy for such breast cancer patients although the outcome is often unsatisfactory. Thus, the development of combination adjuvant therapies is essential for improved prognosis in TNBC patients. In this study, we investigated the efficacy of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for post-mastectomy TNBC patients. Experimental design: From 2008 to 2012, 90 post-mastectomy TNBC patients were included in this retrospective study: 45 cases received chemotherapy alone or with sequential radiotherapy; a further 45 cases received chemotherapy with/without radiotherapy and sequential CIK infusion. Survival analysis showed significantly higher disease-free survival (DFS) rate and overall survival (OS) rates in the CIK treatment group compared with the control group (p=0.0382, p=0.0046, respectively; log-rank test). Multivariate survival analysis showed that CIK adjuvant treatment was an independent prognostic factor for OS of TNBC patients. In subgroup analyses, CIK adjuvant treatment significantly increased the DFS rate of patients with pathological grade III and significantly increased the OS rate of patients in N1, N2, N3-stage, IIB, III TNM stage and with pathological grade III. These data indicate that adjuvant CIK treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of TNBC patients, particularly those with lymph node metastasis, advanced TNM-stage and poor pathological grade.
Abstract:
Jianchuan Xias is a Director of Cell Therapy and Healthcare Research Center and Deputy Director of Biotherapy Center. He completed his BS in Biology (1980-1984) from Nanchang University, Jiangxi, P R, China, and then he joined Harbin Medical Univercity, Haerbin, P R China and completed his MS in Cancer genetics during 1991 to 1994 and also achieved his PhD in Cancer genetics from the same university in 1997. After completion of his PhD, he went for his Postdoctoral studies which he completed in the year 2000 from the Sun Yat-sen University Cancer Center, Guangzhou, P R China. From the year 2000 to 2003 he worked as a Post doctorate at Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Biography:
Galatea Kallergi completed her BSc from the University of Patras, Greece in 1995. She finished her MSc in Cell Biology in 1997. She obtained her PhD in 2003 in Medical School of Crete, Greece. Her Postdoctoral studies were both in Biochemistry and Tumor Biology lab in University of Crete. She is principle investigator in two different EU funding research projects in Medical School of Crete. She has published 19 papers. She works in the field of cancer biology and liquid biopsy. Her work was focus on the identification of new signal transduction pathways in cancer cells and in CTCs.
Abstract:
Circulating tumor cells are considered as a liquid real time biopsy. Their phenotype is not always in concordance with the primary tumor due to cancer evolution. Therefore their characterization is critical before and after therapy in order to determine the response to therapy. Our results on CTCs have shown that CTCs phenotype can change in response to standard chemotherapy. Particularly blood samples from 55 early Triple negative breast cancer patients (TNBC) was examined before and after adjuvant chemotherapy. The expression of Cytokeratins (CK), Estrogen Receptor (ER), Progesterone Receptor (PR), EGFR and HER2 on CTCs was assessed using double immunofluorescent experiments and ARIOL analysis. Our results revealed that CTCs were detected in 39 out of 55 (70.9%) patients with early TNBC tumors before the initiation and in 34 out of 55 (61.8%) after the completion of adjuvant chemotherapy. The frequency of ER-, PR- and HER2- expressing CTCs was significantly reduced post-chemotherapy (p=0.019, p=0.017, 0.018) while the frequency of EGFR was not altered. The percentage of ER-, PR-, HER2- and EGFR-expressing CTCs in metastatic TNBC patients was 26%, 34%, 57% and 62%, respectively. Triple staining experiments revealed that there was no co-expression of CK/EGFR/ER, CK/EGFR/PR or CK/PR/HER2 in CTCs suggesting that ER, PR and EGFR were expressed in different subclones of CTCs in TNBC patients. In conclusion a significant percentage of CTCs in TNBC patients express HER2 and EGFR before treatment, implying that these receptors could be a potential target for the limitation of metastasis. EGFR-expressing CTCs persist after adjuvant chemotherapy, suggesting that additional treatment with EGFR-targeting agents could be used post-chemotherapy to eliminate chemo-resistant CTCs.
Biography:
Hiroshi Maeda is a world renowned expert in macromolecular therapeutics. He was successful in creating theworld first polymeric drug, SMANCS, approved for treatment of hepatoma in Japan. Consequently, he discovered the concept of EPR effect of macromolecular-drugs, ubiquitous mechanism for solid tumor selective targeting of polymeric drugs. He received MS, University of California, Fulbright Fellow, and PhD, MD, Tohoku University. He published more than 450 papers in reputed journals. He was awarded Lifetime-Achievement-Award at Royal-Pharmaceutical-Society, Princess-Takamatsu-Award in Cancer Research, Tomizo-Yoshida-Award, highest award of Japan-Cancer-Assoc., and was also selected as most cited influential scientist in pharmacology by Thomson Reuters 2014.
Abstract:
Cancer is the largest human burdens in health issue. However, its therapy has not really improved much even after emergence of molecular target-drugs, antibody-drugs, liposomal- or polymeric micellar-drugs, etc. We proposed a new concept of cancer drugs 30 years ago using macromolecular drugs (nanomedicines). In this concept the tumor vasculature is the target, which depends on the uniquely different pathophysiology, contrary to normal, such as micro-architecture, excessive production of vascular mediators like bradykinin and NO, and impaired lymphatic clearance from tumor bed. This concept named enhanced permeability and retention (EPR) effect is the basis of tumor-selective drug delivery. This is observed for biocompatible macromolecular-drugs of >50 KDa. It covers, however, only the first step in tumor-delivery, yet it is most critical. Second step is access to tumor cells. The third step is tumor cell-uptake. In the second step, liberation of low-MW-drugs occurs from nanoparticle facilitating rapid diffusion to tumor cell-membrane. In the third step, one can utilize upregulated glucose-transporterfor internalization. We developed recently polymer-(HPMA)-conjugated pirarubicin (THP) via hydrazon bond, which is more selectively cleaved in acidic tumor environment, and liberated the low MW drug which is rapidly taken up into tumor cells more than 30 x of doxorubicin. Using this conjugate our preliminary clinical results showed to be very promising. In drug-dose below toxic level, it exhibits remarkable therapeutic effect. In many solid tumors, blood vessels are frequently embolized and blood flow is hampered. To circumvent this and enhance the EPR effect, we found use of nitroglycerin and inhibitors of angiotensin converting enzyme is highly beneficial, that facilitate tumor drug-delivery 2-3 fold. The EPR effect is also observed in metastatic tumors and inflamed tissues. All in all there are more to come for nanomedicine in cancer therapy, and enhancement of EPR will be highly recommended for tumor delivery without involving serious adverse effects.
- Antimicrobial Agents and Medicines
Location: Room 1
Session Introduction
Hiroyuki Osada
RIKEN Center for Sustainable Resource Science, Japan
Title: Screening of novel antimalarial agents in RIKEN NPDepo
Biography:
Dr. Hiroyuki Osada has received his Ph.D. degree from the University of Tokyo, Japan. He joined RIKEN in 1983 and he became a Deputy Director of RIKEN Center for Sustainable Resource Science from 2013. He discovered KGF/FGF7 when he studied with Dr. S.A. Aaronson in NCI, Bethesda, USA as a visiting scientist (1985-86). As a head of the Antibiotics Laboratory, RIKEN, he discovered many novel bioactive compounds (reveromycin, tryprostatin, etc) from microorganisms. He is serving as an editorial board or advisary member to international journals (Cancer Science, Journal of Antibiotics, ACS Chemical Biology, etc). He is the president of the Society for Actinomycetes, Japan and the Japanese Association for Molecular Target Therapy of Cancer. He received many prestigious awards including the Inhoffen Award (2015). He is the author and co-author of over 350 publications and books (Bioprobes, Protein Targeting with Small Molecules, etc).
Abstract:
Malaria is one of the most serious infectious diseases. Since parasite strains resistant to traditional antimalarial drugs such as chloroquine (CLQ) and artemisinin (ART) derivatives appeared, novel antimalarial agents are required to be developed urgently. I will introduce the screening method and the hit compounds showing the antimalarial activity in this presentation. It is known that malaria parasite has high LDH activity. We established a HTS system using the LDH assay to isolate growth inhibitors of the parasite strain 3D7 cultured in vitro. Using this system, we selected 450 compounds from 17,000 compounds of RIKEN NPDepo (Natural Products Depository) chemical library with 5 µg/mL or less IC90 activity of parasite growth. As the second screening, we evaluated the toxicity toward mouse NIH3T3 and rat NRK cells of these compounds. Eighty six compounds showed selective inhibition against parasite with IC50 values lower than one thirtieth of those toward mammalian cells. Finally, as the third screening, we examined growth inhibitory effect of these 86 compounds on the CLQ resistant parasite strains (K1 and Dd2) and found that 36 compounds were as effective on the resistant strains as on 3D7 strain. NPD10928 (IC50 88 nM) was selected as one of the potent inhibitors against malaria parasites. We administrated NPD10928 to a malaria infectious mouse (ip, 20 mg/kg), and found that the growth of parasite was reduced significantly. In addition, I will introduce other antimalarial agents that were found by our screening.
Minoru Yoshida
RIKEN Center for Sustainable Resource Science, Japan
Title: Chemical genomics for target identification of antifungal theonellamides
Biography:
Minoru Yoshida received his PhD (1986) from the University of Tokyo, where he worked as Assistant and Associate Professors and accomplished mode-of-action studies on trichostatin A (TSA) and leptomycin B (LMB). He identified histone deacetylase and Crm1 as the specific targets of TSA and LMB, respectively. He moved to RIKEN as Chief Scientist in 2002, and has been playing a leading role in chemical biology.His work has unearthed new targets for drug discovery, and several inhibitors of these targets have come into practical use as anticancer drugs. He received many awards including Japan Academy Prize.
Abstract:
Identification of the cellular targets of bioactive small molecules is a major challenge in the development of these molecules as biological tools and therapeutics. Recently, much attention has been drawn to a chemical genetic approach, which uses physical and/or genetic interaction between the compound and its target. Thanks to a wealth of genomic information, genome-wide screening of genetic interaction has become available. We constructed a whole ORF library (ORFeome) of fission yeast and performed reverse proteomics including global analyses of protein subcellular localization (localizome) and protein gel mobility (mobilitome). In combination with these databases and chemical genetic profiling using the strains expressing the ORFeome, we developed a systematic method for drug target identification. This method enabled us to identify the rather unusual mechanism of action of theonellamides (TNMs), marine antifungal cyclic peptides. TNMs were shown to bind to 3beta-hydroxysterols including ergosterol in the fungal cell membrane, thereby inducing abnormal accumulation of 1,3-ï¢-glucan, proving the effectiveness of chemical genomics. Furthermore, we show that in mammalian cells TNMs recognize specific cholesterol-containing membrane domains, induce phase separation of lipid membranes, and induce cell contraction. The usefulness of TNMs as a tool for lipid biology will be discussed.
Shamim Ahmad
Aligarh Muslim University, India
Title: Can we consider honey as an alternate antibacterial and curative medicine in the battle against human ailments specially multi –resistant infections?
Biography:
Dr. Shamim Ahmad is a distinguished senior Professor of Microbiology, Officer In-Charge & Teacher In-Charge (Administrative Affairs) currently working at the Microbiology Section , Institute of Ophthalmology, JN Medical College, Faculty of Medicine , Aligarh Muslim University, India since January, 10, 1983.He has also served as a teaching faculty on deputation from Aligarh for more than 5 years at Faculties of Medicine in the Department of Clinical Microbiology, Al-Arab Medical University, Benghazi, Libya and Department of Medical Microbiology, College of Medicine, Faculty of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia. Prof. Ahmad is the recipient of at least 6 prestigious International Fellowships including "DAAD (W. Germany), "JSPS"(Japan) "ROYAL SOC.-London" (UK), "DAAD" (Germany), "TUBA" (Turkey) and "SAIA" (Slovak Republic). He has published a large number of research papers , book and book chapters in various International journals. He has the credit of supervising / Co-supervising about 47 Ph.D./ M.Phil/ M.Sc. and MS (Ophthalmology) students for their theses beside presenting about 100 research papers and chaired many scientific sessions at various National and International conferences in various countries, having won "Best Paper Award". At present, Prof. Ahmad has honor to be Chief Editor / Editorial Member / Reviewer in the Editorial Boards of at least 43 International Journals of world repute.
Abstract:
Prevalence of alarming multi-antibiotic- resistance among clinical bacteria all over the world has led researchers to think about the development of an effective antibacterial agent to combat many human diseases including multi-resistant pathogens specially involving superbugs-MRSA, VRSA and other organisms. The answer may be hidden in Honey, a natural bee product having an excellent “track record†over 4 000 years of usage as a wound dressing and being easily available over the globe. Honey is a remarkable viscous fluid, prepared by bees from flowers of various plants. Surprisingly, medical uses of Honey for curing various ailments have been endorsed by Holy Quran as “Healer for Mankindâ€, and Prophetic Narrations beside Vedas and Bible books. The Russians made its use in 1st World War to prevent wound infection. Honey has been found to be effective against aerobic, anaerobic, Gram-positive and Gram-negative bacteria. In the recent times, it has been “rediscoveredâ€, with numerous reports of animal models including studies in our laboratory on corneal ulcers’ rabbit models and clinical studies, case reports and randomised controlled trials. The results, thus, have encouraged the use of honey in clinical practice as a natural and safe wound healer. Many International workers including our laboratory have explored Honey’s miracles in various medical fields like Microbiology, Ophthalmology, Surgery, Plastic Surgery, Paediatrics, Gynaecology, Dermatology, Gastroenterology, Dentistry and even cosmetics. Further, A long term in vitro and in vivo research on antibacterial tests and curative properties of Manuka Honey on MRSA,MSSA from Eye patients in UK along with recent treatment trials in dry eye syndromes in human beings in our laboratories in India provides potential prospects and scope of Honey to fight many resistant bacterial population not only in eye infections but many human ailments including alarming untreated and unhealed wounds and ulcers as a possible alternate effective antibacterial option in future particularly involving multi-resistant super bugs like Methicillin- Resistant Staphylococcus aureus – MRSA strains.