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Naturally
evolved from
CEPID/FAPESP Destinguishing features:
1. Research Focus
2. Explicit inclusion of medicinal chemistry
3. Incorporation of young researchers from
outside the state of São Paulo
INTRODUCTIONINTRODUÇÃO
INTRODUCTIONINTRODUÇÃO
TO CONTRIBUTE TO THE BODY OF KNOWLEDGE
CONCERNING THE MOLECULAR BIOLOGY OF
AETIOLOGICAL AGENTS RESPONSIBLE FOR INFECTIOUS
DISEASES THROUGH THE USE OF STRUCTURAL BIOLOGY
WHEREVER POSSIBLE TO APPLY THIS INFORMATION TO ADVANCING
NEW TECHNOLOGIES FOR TREATMENT, PREVENTION, DIAGNOSIS etc.
INBEQMeDI IN A NUTSHELL
INTRODUCTIONINTRODUÇÃO
Leishmaniasis
Schistosomiasis
Chagas’ disease
Malaria
Leptospirosis
GLYCOLYTIC ENZYMES
CRUZAIN
ENZYMES OF AMINO ACID METABOLISM
ENZYMES OF SELENOCYSTEINE BIOSYNTHESIS
E-NTPDases (APYRASES)
PURINE SALVAGE PATHWAY
LEUCYL/PHENYLALANYL tRNA SYNTHASES
ARGINASE
PURINE SALVAGE PATHWAY
E-NTPDases (APYRASES)
SEPTINS
HEME OXIGENASE
PROTEINS FROM THE SIGNAL TRANSDUCTION
CASADE
LIP32 AND LP19
WHAT WE DO
AIMS AND TARGETSOBJETIVOS E METAS
PRODUCTIVITY TARGETS PER YEAR 2009 2010 2011 2012 2013-
Papers published 60/86 70 80 90 100
Genes cloned and expressed 20/30 30 40 40 40
Proteins crystallized 10/12 15 20 20 20
Structures determined by X-rays 10/10 15 20 20 20
Structures determined by NMR 3/0 3 4 4 4
Proteins studied spectroscopically 30/20 40 50 50 50
Protein Structures modeled 10/5 10 10 10 10
Protein targets in screening for compounds 8/4 10 12 12 12
Number of screening assays conducted against
selected targets1000/300 1500 1500 2000 3000
Number of new drug candidates/ compounds
synthesized10/100 20 30 40 50
Projects with industry 2/4 2 3 4 5
Production of new teaching materials 10/5 15 20 20 30
Organization of Science Education Events 5/15 8 10 10 10
No. of new pages at the CBME/ INBEQMeDI
Internet site10/10 15 20 30 30
No. of lectures/courses 40/35 50 50 50 60
AIMS AND TARGETSOBJETIVOS E METAS
Leishmania - Leishmanioses
Via de recuperação de purinonucleotídeos
- fosforibosiltransferases1 artigo
Apyrases de Leishmania
Via de sintese de Selenocisteínas 3 artigosInvestigação da via "N-end rule" em
Leishmania
Arginase de Leishmania
Busca por inibidores 1 artigo
Identificação de novos alvos moleculares 1 artigo
Schistosoma mansoni - Schistossomose
Enzimas envolvidas na via de recuperação
de nucleotídeos (Purinas e Pirimidinas)2 artigos
Isolamento e caracterização de septinas
de S. mansoni
Apyrases de S. mansoni
Busca por inibidores 2 artigos
Identificação de novos alvos moleculares 4 artigos
Plasmodium falciparum - Malaria
Via de sinalização em Plasmodium 4 artigos
Leptospira sp - Leptospirose
Estudos estruturais de lipoproteínas de
superfície4 artigos
Outros alvos 10 artigos
Revisões 11 artigos
Outros artigos 32 artigos
Trypnosoma cruzi - Doença de Chagas
Enzimas envolvidas no metabolismo
energético de carboidratos (Glicolise, via
das
pentoses fosfato e gliconeogênese)
8 artigos
Protease (Cruzaína) 2 artigos
Metabolismo de Aminoacidos 2 artigos
Via de sintese de Selenocisteínas 2 artigos
Nucleosídeo Difosfatase (NTPDase) 2 artigos
Busca por inibidores 4 artigos
Identificação de novos alvos moleculares 3 artigos
INTERNATIONALIZATIONINSERÇÃO INTERNACIONAL
Jean Christophe
Giard -
University of
Caen, France
Anne Cleasby –
Astex
Therapeutics
Bill Hunter
University of Dundee
Deiter Soll
Yale, USA
Walter Leal,
Davis
Alejandro Vila
Rosário
Barbara Papadopoulou
QuebécPeter Myler
Seattle
Christine Orengo
London
Isidro González Collado
Cádiz, Spain
Sean Brady
Rockerfeller, USA
Frederick Ausubel
Harvard Medical School
Christian Doerg
Switzerland
Dobiopan Chakrabati
Florida, USA
Asko Uri
Tartu, Estonia
Andrew Thomas
New Jersey
Martin Bootman
Cambridge, UK
Michael Nathanson
Yale, USA
Alison Smith
Cambridge, UK
Allan Wilson
York, UK
Hans Kalbitzer
Regensburg, Germany
Jack freed
Cornell, USA
Paolo Mariana
Marche, Italy
Georgina Tonarelli,
Sta. Fá, Argentina
Robert Ryan
Cork, Ireland
Alexander Tropsha
North Carolina, USA
Daniel Rauh,
Dortmund, Germany
Billy Day,
Pittsburgh, USA
Paul Michels,
Brussels, Belgium
Frederic Bringaud
Bordeaux, France
Trevor Anderson,
Pieterrmarizburg, RSA
INTERNATIONALIZATIONINSERÇÃO INTERNACIONAL
INTERNATIONAL NATIONAL
69 17
PUBLICATIONS
CONGRESSOS
RESEARCHERS
101
25
INVITED TALKS ABROAD
INTERNATIONALIZATIONINSERÇÃO INTERNACIONAL
XVIIIth ANNUAL MEETING OF
INPEC
TEACHING STRUCTURAL
BIOLOGY IN SOUTH AFRICA
ARGENTINA
CHILE
2ND Brazilian Conference on Natural
Products and XXVIII Meeting on
Micromolecular Evolution,
Systematics and Ecology
Brazilian meeting on Organic
Synthesis
Workshop on Epidemiological and
Molecular Approaches to Understand
Malaria Infection
XXXIX Summer School in Chemistry
UFSCar
INTERNATIONAL WORSHOP ON
SPECTROSCOPY IN BIOLOGY
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
CO2H
HO
CO2H
HO
IC50 = 28 M (GAPDH)
IC50 = 66 M (in vitro against T. cruzi trypomastigote form)
SOCl2NaBH4
H
O
OH ClNHMe2
NMe2
8a-c: n = 4,6,8/R = OTHP
8d,e: n = 6,9/R = CH3
2 3m-anisaldehyde
OMe OMe OMe
4
OMe
6
R
CO2Et
OMe
( )n
5
OMe
CO2Et
ClPPh3
CO2Et
OMe
PPh3+Cl -
ClCO2CH2CH3
n-BuLi
CO2H
OH
H
O
( )6
CO2H
OH
R( )n( ) R
CO2Et
OH
nNaOH
9a-c: n = 4,6,8/R = OH
9d,e: n = 6,9/R = CH3
10a-c: n = 4,6,8/R = OH
10d,e: n = 6,9/R = CH3
(ClCO)2
DMSO
11
99% 96% 94%
42%
82%
or BBr3 (d,e)
82%
68-85%
73%
2) H2, Pd /C
95-98%
1) LHMDSR(CH2)nCHO
18-51%
AlCl3 (a-c)
42-64%
Inhibitor
NAD+ G-3-P
Ki (µM)
Ki
(µM)
Ki
(µM)
Ki
(µM)
1 4 6 2 4
10e 5 43 4 38
Anacardic acids
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
The inhibitor is bound to a hydrophobic
pocket located at the interfacial region
among subunits A (orange), C (cyan) and
A’ (green).
1/[NAD+] x 10
-4 .min
-1
-20 -10 0 10 20 30
1/[N
AD
H] x 1
0-4
M
.min
-1
0
200
400
600
800
1000
NAD+ vs V1
NAD+ vs V2
NAD+ vs V3
NAD+ vs V4
NAD+ vs V5
[1] - 0.0 µM
[1] - 42.5 µM
[1] - 45.0 µM
[1] - 50.0 µM
[1] - 47.5 µM
Kinetic analysis shows then inibitors to
be non-competitive
GAPDH
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
Guido RV, Oliva G, Montanari CA,
Andricopulo AD. J. Chem. Inf. Model. 2008,
48, 918-929.
Trossini GH, Guido RVC, Oliva G, Ferreira
EI, Andricopulo AD. J. Mol. Graph. Model.,
2009, 28, 3–11.
Salum LB, Andricopulo AD. Mol. Divers., 2009, 13, 277–285.
Salum LB, Andricopulo AD. Expert Opin. Drug Discov., 2010, 5,
405-412.
A COMBINATION OF MOLECULAR MODELLING AND QSAR
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
Targeting enzymes for rational drug design:E-NTPDases (apyrases) from Trypanosoma cruzi and Leishmaniaspas new targets
T. cruzi has only one E-
NTPDase
Leishmania has two E-
NTPDases
This paper describes for the first
time the main role of E-NTPDase
as T. cruzi infectivity and virulence
factor and highlighted it as new
good target to Chagas disease
chemotherapy.
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
NTPDase-1 inhibition leads to
significant decreasing in in
vitro infectivity
NTPDase-1 inhibition leads to
significant lower virulence
levels and higher animal
survilance.
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
Puri-Pyrimidome Primer Amplified Cloned Express Soluble Purified
Crystal
screening Crystals Diffraction Structure Kinetics
Adenosina Kinase 1
Adenosina Kinase 2
Adenosina deaminase 1
Adenosina deaminase 2
APRT
PNP2
HGPRT
Tymidilate synthase
Uridine phosphorylase
NDPK
DHFR
Cytidine deaminase
PNP2_PMAL
Mtap_New
SHMT Citoplasmatic
SHMT Mithocondrial
Dihydroorotate dehydrogenase
Cytidylate kinase
Deoxycytidylate deaminase
Uridine cytidine kinase I.I
Uridine cytidine kinase I.II
Adenylate kinase 1
Adenylate kinase 2
CAD
Guanylate kinase
January 2009
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
Puri-Pyrimidome Primer Amplified Cloned Express Soluble Purified
Crystal
screening Crystals Diffraction Structure Kinetics
Adenosina Kinase 1
Adenosina Kinase 2
Adenosina deaminase 1
Adenosina deaminase 2
APRT
PNP2
HGPRT
Timydilate synthase
UP_D
UP_G
UP_D/G
NDPK
DHFR
Cytidine deaminase
MTAP
SHMT Citoplasmatic
SHMT Mithocondrial
Dihydroorotate dehydrogenase
Cytidylate kinase
Deoxycytidylate deaminase
Uridine cytidine kinase 1
Uridine cytidine kinase 2
Adenylate kinase 1
Adenylate kinase 2
CAD
Guanylate kinase
January 2010
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
Puri-Pyrimidome Primer Amplified Cloned Express Soluble Purified
Crystal
screening Crystals Diffraction Structure Kinetics
Adenosina Kinase 1
Adenosina Kinase 2
Adenosina deaminase 1
Adenosina deaminase 2
APRT
PNP2
HGPRT
Timydilate synthase
UP_D
UP_G
UP_D/G
NDPK
DHFR
Cytidine deaminase
MTAP
SHMT Citoplasmatic
SHMT Mithocondrial
Dihydroorotate dehydrogenase
Cytidylate kinase
Deoxycytidylate deaminase
Uridine cytidine kinase 1
Uridine cytidine kinase 2
Adenylate kinase 1
Adenylate kinase 2
CAD
Guanylate kinase
November 2010
RESEARCH PROGRESSAVANÇO DO ESTADO DA ARTE
Adenylate kinase Uridine phosphorylase Dihydrofolate reductase
Adenosine kinase Methylthioadenosine phosphorylase
MANAGEMENT COMMITTEECOMITÊ GESTOR
Glaucius Oliva Project Coordinator
Richard Garratt Vice-coordinator
Otavio Thiemann Innovation
Leila Beltramini Outreach
Paulo Cesar Vieira External Lab. Representative
January 2009
July 2010
April 2010
INTERNAL WORKSHOPS
HR – QUANTITATIVE ANALYSISQUANTITATIVOS
STUDENTS FINISHING (2009-2010) - EARLY DAYS
IC MSc PhD PD
5 4 3 4
HR – POTENTIAL GAINSPOTENCIAL DE APROVEITAMENTO DOS RH FORMADOS
PAST RESULTS PROSPECTS FOR THE FUTURE
MULTI-DISCIPINARITY LEADS TO OPPORTUNITIES
UNIVERSITIES
RESEARCH INSTITUTES
COMPANIES
SPIN-OFFS
HR – PRIVATE SECTORINTERAÇÃO COM SETOR PRODUTIVO
PAST RESULTS FUTURE PROSPECTS
Eurofarma
- Monique Mantovani
- Cecília Shusmater
Cristália
- Ney Leite
- Karime Chinelato
GE Healthcare
- Marcos Calgaro
- Franc Alarcon
Novatis
- Gisele Tavares
EMS
- Patricia Baraldi
CNPEM
- André Ambrósio
- Sandra Martha Gomes Dias
- Artur Cordeiro
- Ana Carolina Filgueira
- Ana Paula Citadini
SLS, Switzerland
Ezequiel Panepucci
Soleil, France
Beatriz Guimarães
OUTREACH
Production and evaluation of educational resources.
Scientific and educational events at INBEQMeD building.
Activities aimed towards students and teachers.
Contribute to science centers and partner nuclei from severalcities and states of Brazil.
Continued education courses for teachers from public schools of São Paulo State
EDUCATION IN SCIENCEEDUCACÃO PARA A CIÊNCIA
PHYSICAL MODELS
DNA AMINO ACIDS PROTEINSMAGAZINES
SOFTWARE CARD GAMES BOARD GAMES
Interactive software - parasites
DemoChagas.wmv
EDUCATION IN SCIENCEEDUCACÃO PARA A CIÊNCIA
INTERACTION WITH
SCHOOLSINTERAÇÃO COM ENSINO BÁSICO
TEACHER TRAINING
VIA THE STATE OF SÃO PAULO EDUCATION DEPARTMENT
Biologia Molecular Estrutural e Suas
Relações com a Biotecnologia - 2009
Biotecnologia: atualização em temas e
tecnologias associadas - 2010
www.rededosaber.sp.gov.br/videoteca/biotecnology (select VC)
RESULT: 556 Pedagogical coordinators from 92 regions of the
States have particpated in these workshops
Video conferences Speakers
Cells – a structure based on a large assembly ofmacromolecular interactions.
Leila M. Beltramini
Genome Organization and Function of the Cell: Structure ofDNA.
Nelma R. S. Bossolan
Genetic engineering, transgenic organisms andrecombinant DNA technology.
Ana Paula U. Araujo
Property of Organic Compounds and Chemical Bonds. José Luiz Lopes
Synthesis, Structure and Function of Proteins Leila M. Beltramini
Biotechnology and the discovery of new medicines andvaccines: a long way of research.
Glaucius Oliva
The electromagnetic spectrum: applications, its effects on health and the environment.
Claudia E. Munte
Neglected Infectious Diseases: social, environmental and economic issues.
Nelma R. S. Bossolan
Nanomaterials: definition, properties and applications. Antônio Carlos Hernandes
INTERACTION WITH
SCHOOLSINTERAÇÃO COM ENSINO BÁSICO
Atividades presenciais
8 e 9 Outubro 2009
Serra Negra - SP
INTERACTION WITH
SCHOOLSINTERAÇÃO COM ENSINO BÁSICO
MULTIPLICATION VIA LOCAL COURSES
DISTRICT teachers year
SUL-3 40 2010
Bauru 42 2010
José Bonifácio 20 2010
Tupã 40 2010
Pontal Paranapanepa 80 2011
Registro 80 2011
Catanduva 40 2011
Limeira 40 2011
Franca 60 2011
INTERACTION WITH
SCHOOLSINTERAÇÃO COM ENSINO BÁSICO
GOVERNMENTAL POLICYPOLÍTICAS PÚBLICAS
Medicinal Chemistry Centre for Chagas
Disease in Brazil
World Health Organization
~ 200 coumpounds
designed and
synthesized
~100 times improvement
on binding affinity of
benznidazol
GOVERNMENTAL POLICYPOLÍTICAS PÚBLICAS
INTERACTION WITH THE PRIVATE SECTORINTERAÇÃO COM O SETOR EMPRESARIAL
Prof. Dr. Ilana Lopes B. C. Camargo
Pfizer Invetigator-Initiated Research:
Molecular epidemiologic study of Vancomycin-Resistant Enterococci isolated in Belo Horizonte (MG, Brazil) and
evaluation of in vitro susceptibility to new drugs available.
Prof. Dr. Otavio H. Thiemann, Glaucius Oliva and Igor Polikarpov
EMS Sigma Farma/FINEP:
"PRODUÇÃO DE BIOFÁRMACO E DE SEU DERIVADO SINTÉTICO NO BRASIL”
Profa. A. Correa
EMS Sigma Farma
“USE OF 4-QUINOLINONES AND QUINOLINES AND USE THEREOF”
Profa. Dra. Ana Paula Araújo
Prof. Dr. Ilana Lopes B. C. Camargo
Novartis:
Epidemiological Study of Methicillin-resistant Staphylococcus aureus isolated from infected patients during a
hospital surveillance period.
Prof. Dr. Otavio H. Thiemann
Sanofi-Aventis:
Drug Development for the Tratment of Chagas´Disease.
Profa. Dra. Ana Paula Araújo, Richard Garratt
Alvos/Ourofino “Desenvolvimento de vacina anti-helmintica baseado em Sm14
LAM - Educacional
KITS FOR BUILDING THE MOLECULES OF LIFE
Eli Lilly
Cristália
SIG
NE
D C
ON
TR
AC
TS
IN N
EG
OT
IAT
ION
CO
NS
ULTA
NC
Y
ED
UC
AT
ION
PR
OS
PE
CT
ION
PATENTSPATENTES
RECENT PATENT APPLICATIONS (2009-2010)
Patent Request No: PI0804314-0 A2
Inventors: CELIA REGINA DA SILVA GARCIA / BETTINA MALNIC / LUCIANA MADEIRA DA SILVA /
PEDRO ALEXANDRE FAVORETTO GALANTE
Title: COMPOSICAO FARMACEUTICA, METODO DE TRIAGEM DE DROGAS E METODO DE
TRATAMENTO PARA MALARIA
Patent Request No: PI0000221001833362
Inventors: Fietto, J.L.R, FRANCISCO DE SOUZA, r & ALMEIDA, M.R.
Title: NTPDASES RECOMBINANTES, USO NA PRODUÇÃO DE KIT DE DIAGNÓSTICO PARA
DETECÇÃO DE ANTICORPOS NAS LEISHMANIOSES CAUSADAS POR ESPÉCIES DE GÊNERO
LEISHMANIA
PATENTSPATENTES
PREVIOUSLY EXISTING PATENTS OR PENDING
APPLICATIONS RELATED TO INBEQMeDI ACTIVITIES
Galler, R., Bonaldo, M. & Garratt, R.C. “Use of flavivirus for the expression of protein epitopes and
development of new live attenuated vaccine virus to immunize against flavivirus and other infectious
agents” : Filed UK, No. GB 0105877.5, 09/03/01 (PCT/BR02/00036, 08/03/02)
Tendler, M., Garratt, R.C., Katz, N., Simpson, A.J.G., Barrientos, F.J.A., Vilar, M.M. & Almeida,
M.S.S. “Synthetic Active Peptide Fragments” : Filed USPTO, US 10/113,946, 02/04/02 : PCT
(PCT/BR03/00051, 01/04/03)
Garratt, R.C. & Abel, L.D.S. Modelo Tridimensional para representar estrutura ou parte de estrutura
protéica e “kit” : Depósito PI 0300610-7 : Extendido via: PCT (PCT/BR2004/000014, 18/02/04)
Beltramini, L.M & Araújo, A.P.U. “Modelo tridimensional para representar molécula ou parte de
molécula de acido nucleico e kit”, Depósito : PI 0301512-2, 16/05/03
Beltramini L.M. & Silva, A. Patent filed re “Unidades Representativas de Aminoácidos para Construir
Estruturas Primárias e Secundárias de Proteínas”
Correa, A.G., Baraldi, P.T. Soares, A.M. “Process for the preparation and pharmaceutical formulations of
4-quinolinones and quinolines and use thereof” PCT WO 2008144865, PI0701664-6
TECHNOLOGY TRANSFERTRANSFERÊNCIA DE TECNOLOGIA
LAM EDUCACIONAL, INDÚSTRIA E COMÉRCIO
DE MATERIAIS PARA ENSINO LTDASão Carlos
Amino acids Nucleic acids Proteins
OUTREACH SPIN-OFF COMPANY
Pre-built models
School kits