Metabolomics Workshop - Programa BIOTA/FAPESP

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BIOTA/FAPESP Scientific Program for the 1st Semester, 2010
BIOprospecTA WORKSHOP
International Workshop on
METABOLOMICS IN THE CONTEXT OF SYSTEMS BIOLOGY: A
RATIONAL APPROACH TO SEARCH FOR LEAD MOLECULES FROM
NATURE
Part of 2010´s Scientific Program of Biota + 10 FAPESP
Carlos A. Joly (Coordinator of Biota Program)
Célio Haddad
Luciano verdade
Mariana Cabral
Vanderlan da S. Bolzani (Coordinator of the Workshop)
February, 25-26, 2010 - FAPESP Auditorium
Secretaria do Instituto Virtual da Biodiversidade
Programa BIOTA/FAPESP
Departamento de Biologia Vegetal – IB/UNICAMP
Caixa Posta 6109 – 13093-970 Campinas/SP
Fone/Fax (19) 3521 6168
RESUMO DO PROJETO
O projeto em pauta – International Workshop on METABOLOMICS IN THE
CONTEXT OF SYSTEMS BIOLOGY: A RATIONAL APPROACH TO SEARCH
FOR LEAD MOLECULES FROM NATURE tem como objetivo principal estabelecer
discussões em torno de uma massa crítica de pesquisadores no Estado de são
Paulo que atua em Química de Produtos Naturais, objetivando a pesquisa
multidisciplinar de bioprospecção da biodiversidade remanescente no Estado,
baseada nos últimos avanços do estado-da-arte das ciências químicas e biológicas.
O Programa Biota, após 10 anos de existência, se organiza para novos desafios
sobre a pesquisa multidisciplinar com a biodiversidade local, principalmente àquela
voltada para o desenvolvimento sustentável das espécies que foram mapeadas nas
áreas de Cerrado e da Mata Atlântica, ocorrentes no estado de São Paulo. O
workshop foi idealizado dentro de uma nova filosofia da FAPESP, dedicada as
discussões em temas relevantes dos Programas financiados por esta agência de
fomento à pesquisa. Com forte componente transdisciplinar, este workshop trará
avanços substanciais ao programa BIOTA-FAPESP, tendo em conta a temática
científica escolhida para discussão durante os dois dias de discussão. As
conferências que serão apresentadas fundamentam-se nos últimos avanços da
química de produtos naturais e da farmacologia e permitirão um bom norteamento
para a continuidade do Sub-programa BIOprospecTA para os próximos 10 anos.
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ABSTRACT OF THE PROJECT
The guideline project - International Workshop on Metabolomics IN THE CONTEXT
OF SYSTEMS BIOLOGY: A RATIONAL APPROACH TO SEARCH FOR LEAD
MOLECULES FROM NATURE has as main goal to enter into discussions around a
critical mass of researchers in the State of São Paulo dedicated to the Chemistry
Natural Products. The efforts to create a multidisciplinary research aimed at
bioprospecting of remaining biodiversity in the state, based on the latest advances in
state-of-the art of chemical and biological sciences will establish a new paradigm on
the field of Natural Products dedicated to drug discovery. After 10 years, the Biota
Program is being reorganized to reach new challenges, with a focus on
multidisciplinary research on our biodiversity, especially those related to the species
that have already been mapped in the areas of Cerrado and Atlantic Forest, of São
Paulo. The workshop was designed within a new philosophy of FAPESP, dedicated
to discussions on relevant topics of its Programs, which are being funded by this
agency. With a strong interdisciplinary component, this workshop will bring
substantial improvements to the BIOTA-FAPESP, taking into account the scientific
field chosen for discussion during two days. All conferences will be presented by
renowned researchers from USA, Europe and Brazil, based on the latest advances
in natural products chemistry and pharmacology, and will contribute for the continuity
of the Bioprospecta sub-program for the next 10 years.
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The importance of the topic
The focus on innovation in current drug discovery is one new targets, yet compound
efficacy and safety in biological models disease – not target selection – are the
criteria that determine which drug candidates enter to the clinic. Modern
bioprospecting should consider a biology-driven approach to search for new drugs,
which involves screening compounds by automated responses profiling in disease
models based on complex human-cell systems. Drug discovery through cell systems
biology could significantly reduce the time and cost of new drug development.
Cell systems biology approach have been recently used to explore the potential
implications of a drug discovery paradigm in which complex biological responses are
used directly to screen for and select lead molecules.
Recent studies suggest that primary human cell systems can be designed to model
many aspects of disease biology, and robust, automated assays can be engineered
to detect and discriminate a surprising breadth of disease-relevant pathways and
mechanisms. Most of theses assays benefits from principles of systems biology, and
mimic the complexity of disease process by incorporating multiple cell types and
activating multiple pathways together.
Objectives
The main goal of this workshop is to show the last advances in the state-of-art of
drug discovery, which has a practical approach to systems biology because this
focus directly measure disease-relevant cellular responses without the need for
complex in silico models whose application to predicting human cell responses,
except in prescribed settings, is many years in the future.
Most of today´s successful drugs are the chemical descendent of natural products or
bioactive agents that were originally selected for their biological effects, and so far,
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we have a fantastic source material to develop advance research aiming bioproducts
(agrochemicals, fragrances, medicines and nutraceuticals) from the remaining Sao
Paulo State biodiversity. The workshop will be held in to days:
Background and Significance
Certainly, the use of natural products has been the single most successful strategy in
the discovery of novel medicines [Harvey, 2000]. Most of the medical breakthroughs
are based on natural products, with for example, natural products as ligands for
many of the known receptors and enzymes inhibition assays. In 1999, half of the top
20 best-selling drugs were natural products, and their total sales amounted to US$
16 billions [Harvey, 2000].
The importance of natural products is evidenced by the new chemical entities (NCE)
approved by regulatory authorities around the world in the past decade. Of the ca.
500 NCE, introduced in the period, nearly half are from natural resources [Cragg,
1997]. In 1999, the approval of the natural alkaloid galantamine as a medicine to
treat Alzheimer’s disease shows that natural compounds from plants will continue to
reach the market [Ferris, 2001].
The reasons for the continuous success of natural products as leads for drug
development are several. First of all, because natural products are biosynthesized in
natura to have an activity, e.g. as defense against microbial infections or predators,
which means that the structures have drug-like properties that are selected during
the evolution to bind to some target proteins in other organisms. A second reason –
that seems – a chemical perspective, they are clearly different from what synthetic
chemistry will achieve. The natural products are characterized by great structural
complexity and obviously different and complementary to the synthetic compounds
[Newman et al., 2003]
Since the beginning of civilization, mankind has been exploring nature for medicines,
as well as other applications. This has resulted, among others, in the discovery long
ago of opium alkaloids (many antinociceptives based on morphine), cocaine (local
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anesthetic), cinchone alkaloids (antimalarial compounds based on quinine), salicylic
acid, and various tropane alkaloids contained in plants. (Newman et al., 2003). As
can be learned from this review, the process continues in modern development and
some examples are given (Table 1). In addition, ethnomedical plant-use data in
many
forms
has
been
heavily
utilized
in
the
development
of
novel
phytopharmaceuticals, providing a major focus in global health care, as well as
contributing substantially to the drug development process, especially in developing
countries [Farnsworth, 2000].
A major difference between the old times and present day drug development is
probably that in the past, people tested the medicines directly on humans, whereas
nowadays the starting point is a screening at molecular level, or in some cases on
cellular level (e.g. antibiotics and antitumor compounds). This workshop deals with
the most advanced in drug discovery sciences, and so far will bring a great
contribution for the future of this important research area in Brazil.
Table 1. Drugs of natural origin or derivatives that were on the market before
synthetic drugsa,b. For some of these drugs, synthetic counterparts have not yet
been developed*.
Natural Compound
Mode of Action
Amphotericin B
Artemisinin
Atropine
Avermectin
Camptothecin
Dicoumarol
Digoxin
Ecteinascidin 743
Ephedrine
Ergocornine
Fusidic acid
Gentamycin
Griseofulvin
Harmaline
Heparin
Lovastatin
Cell membrane permeability
Interation with haem
Muscarinic
acetylcholine
antagonist
Cl- channel activator
Topoisomerase I inhibitor
Vitamin K antagonist
Na+-K+-ATPase inhibitor
Transcription factor antagonist
β-adrenoceptor agonist
Dopamine receptor agonist
Interleukin antagonist
Protein synthesis inhibitor
Mitosis inhibitor
MAO inhibitor
Antithrombin III activator
HMG-CoA synthetase inhibitor
Morphine
Paclitaxel
Opioid receptor agonist
Microtubule stabilization
receptor
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(Semi)
synthetic
drug
Not yet described*
Arthemether
Butylscopolamine
Selamectin
Irinothecan
Acenocoumarol
Acetyldigoxin
Not yet described*
Isoprenaline
Bromocryptine
Not yet described*
Metamycin
Not yet described*
Pargyline, deprenyl
Not yet described*
Simvastatin,
pravastatin
Pethidine, fentanyl
Taxotere
a
Papaverin
Penicillin G
Physostigmine
Podophyllotoxin
Rampamycin
Quinidine
Salicilic acid
Teprotide
Tetracyclins
∆9-Tetrahydrocannabinol
d-Tubocurarine
Phosphodiesterase inhibitor
Transpeptidase inhibitor
Cholinesterase inhibitor
Topoisomerase II inhibitor
Calcineurin antagonist
K+ channel antagonist
Cyclooxygenase inihibitor
ACE inhibitor
Protein Synthesis inhibitor
Cannabinol receptor agonist
Nicotinic acetylcholine receptor antagonist
Yohimbine
Vincristine
α2-Adrenoceptor antagonist
DNA polymerase inibitor
Sildenafil
Ampicillin, cyclacillin
Neostigmine
Etoposide
Not yet described*
Disopyramide
Acetylsalicilic acid
Captopril, elanapril
Doxycycline
Nabilone
Vecuronium,
pancuronium
Idazoxan
Vendesine
Solvay Pharmaceutical, Dept of intellectual Property and Scientific Information, email: [email protected]
Lars Bohlin-University of Uppsala, Division of Pharmacognosy, Dept of Medicinal Chemistry, PO Box 574, 751 23 Uppsala,
Sweden.
b
References
Ferris, S. HClinical Therapeutics. 2001, 23, 3.
Harvey, A. Drug Discovery Today 2000, 5, 294.
Newman, T. J., Cragg, G. M., Sander, K. M. J. Nat. Prods. 2003, 66, 1022;
Newman D. J.; Cragg, G. M.; J. Nat. Prod. 2007, 70, 461.
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Program of the Workshop
February 25/2010
8:00 h Registration
8:40 h Open Ceremony
Carlos A. Joly (Coordinator - Biota-FAPESP)
Vanderlan Bolzani (Chair of the Workshop)
Symposium I: Metabolomics and Systems biology as a tool for new drugs
discovery
9:00-9:50 Systems Biology: a Gateway to Novel Discoveries
Robert Verpoorte (Leiden University – Holland )
9:50-10:15 Integration of Structure- and Ligands Based Drug Design
Approaches for the Discovery of Lead Compounds from Natural Products
Adriano Andricopulo (IF-USP, São Carlos-SP)
10:15-10:40 Inhibition of Photophosphorylation and Electron Transport Chain in
Thylakoids by Natural Products
Maria Fátima das G. Fernandes da Silva (UFSCAR, São Carlos -SP)
10:40-11:05 The Development of New Products from Brazilian Biodiversity
Emerson Queiroz (Laboratório Aché, São Paulo, SP)
11:05- 11:20 Coffee break
11:20:12:10h MS-based Metabolomic Approaches Combined with MicroflowNMR Methods for the Search of Original Stress Induced Biomarkers in Plants
Jean-Luc Wolfender (Université de Genève)
12:10-12:30 Discussion
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12:30-14:00 h Lunch
Symposium II: Plants and Associate Microorganisms as Potential source of
New Biologically Active Molecules
14:00-14:50 Systems Biology of Symbiotic Bacteria and the Search for New
Biologically Active Molecules
Jon Clardy (Harvard Medical School, USA)
14:50-15:15h Exploring Microbial Interactions in Natural Products Research
Monica Talarico Puppo (FCF-USP, Ribeirão Preto, SP)
15:15-15:40h Search for Potential Antitumoral, Antioxidant, Anti-inflammatory,
Antifungal, Antidiabetic, Acetylcholinesterase and Myeloperoxidase Inhibitory
Natural Compounds from Cerrado and Atlantic Forest
Dulce Helena Siqueira Silva (IQ-UNESP, Araraquara, SP)
15:40-16:00h Coffee Break
16:00:16: 25h Footprinting of the ‘Final-fate Compounds’ in Systems Biology:
Reading the Nature’s Message
Mario Palma (IB-UNESP-Rio Claro, SP)
16:25:16:50h Molecular diversity among basal Angiosperms
Massuo Jorge Kato (IQ-USP, São Paulo, SP)
16:50-17:40h Cultured Cyanobacteria: A Promising Source for Novel Bioactive
Natural Products
Jimmy Orjala (University of Illinois at Chicago, USA)
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February 26/2010
Symposium III: New Advance Methodology for the Search Drug Discovery
9:00-9:50 h Arthur Edison (Florida State University - USA)
9:50-9:15h ESI-MS/MS Techniques and Applications for the Analysis of Natural
Products
Norberto Peporine Lopes (FCF-USP, Ribeirão Preto, SP)
9:15-9:40h Search for highly efficient alcohol dehydrogenases from
microorganisms to be applied in enantioselective oxidation of secondary
alcohols and bioreduction of ketones
Leandro Helgueira Andrade (IQ-USP, São Paulo, SP)
9:40-10:05 Novel application of 2D and 3D-similarity searches to assess
compound selectivity among Cytochrome P450 2C9, 2D6 and 3A4 substrates
Carlos Alberto Montanari (IQ-USP, São Carlos, SP)
10:05-10:30 Coffee break
10: 30- 11:20h Innovative Strategies to Enhance Structural Diversity of Natural
Products and Discovery of their New Uses
A. A. Leslie Gunatilaka (The University of Arizona, USA)
11:20- 12:30h Discussion
12:30 h Lunch
Symposium IV: New Approach to Screening Biodiversity Source Materials and
New Trends in Pharmacology and Toxicology to Select New Targets
14:00-14:50 h Taxol, Tubulin and Tumors: Challenges in the New Era of Cancer
Therapeutics
Suzan Band Horwitz (Albert Einstein College of Medicine – USA)
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14:50-15:20h
International Workshop on Metabolomics in the Context of
Systems Biology: a Rational Approach to Search for Lead Molecules from
Nature
Newton G. Castro (UFRJ, Rio de Janeiro)
15:20-15:45h Decoding the Signaling Network in Malaria Parasites
Célia Regina Silva Garcia (USP, São Paulo, SP)
15: 45-16:10 h Recent Studies of Natural Products Isolated From Brazilian
Plants: Evaluation of Antigenotoxicity, Antimutagenicity and Antitumoral
Assays
Christiane Pienna Soares (Fac. De Farmácia, UNESP – Araraquara, SP)
16:15-16:30 Coffee break
16:30:17:00h
Novel Heparinomimetics with
Cardiovascular and Inflammatory Disorders
Potential
Therapeutic
Helena B. Nader (Escola Paulista de Medicina, SP)
Close Remarks
17:30-18:00 - Vanderlan da Silva Bolzani (IQ-UNESP, Araraquara, SP)
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Metabolomics Workshop - Programa BIOTA/FAPESP

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