INTRODUCTION - Portal IFSC · Identificação de novos alvos moleculares 3 artigos....

INTRODUCTION

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


WHO WE ARE


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


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

RESEARCH

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


INTERNATIONAL NATIONAL

69 17

PUBLICATIONS

CONGRESSOS

RESEARCHERS

101

25

INVITED TALKS ABROAD


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


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


A COMMON APPROACH – PNP FROM S. mansoni


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


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.


NTPDase-1 inhibition leads to

significant decreasing in in

vitro infectivity

NTPDase-1 inhibition leads to

significant lower virulence

levels and higher animal

survilance.


SCHISTOSOME PURINOME/PYRIMIDOME

PROJECT


Puri-Pyrimidome Primer Amplified Cloned Express Soluble Purified

Crystal

screening Crystals Diffraction Structure Kinetics

Adenosina Kinase 1

Adenosina Kinase 2

Adenosina deaminase 1


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



Crystal


Adenosina Kinase 1

Adenosina Kinase 2



APRT

PNP2

HGPRT

Timydilate synthase

UP_D

UP_G

UP_D/G

NDPK

DHFR

Cytidine deaminase

MTAP

SHMT Citoplasmatic

SHMT Mithocondrial


Cytidylate kinase


Uridine cytidine kinase 1


Adenylate kinase 1

Adenylate kinase 2

CAD

Guanylate kinase

January 2010



Crystal


Adenosina Kinase 1

Adenosina Kinase 2



APRT

PNP2

HGPRT

Timydilate synthase

UP_D

UP_G

UP_D/G

NDPK

DHFR

Cytidine deaminase

MTAP

SHMT Citoplasmatic

SHMT Mithocondrial


Cytidylate kinase




Adenylate kinase 1

Adenylate kinase 2

CAD

Guanylate kinase

November 2010


Adenylate kinase Uridine phosphorylase Dihydrofolate reductase

Adenosine kinase Methylthioadenosine phosphorylase


HONEYBEE ESRF

THE IMPORTANCE OF TECHNOLOGY

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

NETWORK FORMATIONFORMAÇÃO DE REDE DE PESQUISA

INTERNAL WORKSHOPS

SCIENTIFIC PRODUCTIVITYPRODUÃO CIENTÍFICA

HUMAN RESOURCESFORMAÇÃO DE RECURSOS HUMANOS

HR – QUANTITATIVE ANALYSISQUANTITATIVOS

OVERALL FIGURES

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

http://www.abtlus.org.br/

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

OUTREACHTRANSFERÊNCIA DE CONHECIMENTO PARA A SOCIEDADE

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

RELATING TO SOCIETYRELACIONAMENTO COM A SOCIEDADE

video

EDUCATION IN SCIENCEEDUCACÃO PARA A CIÊNCIA

PHYSICAL MODELS

DNA AMINO ACIDS PROTEINSMAGAZINES

SOFTWARE CARD GAMES BOARD GAMES

Interactive software - parasites

DemoChagas.wmv


DemoChagas.wmv

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

http://www.rededosaber.sp.gov.br/videoteca/biotecnology

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


Atividades presenciais

8 e 9 Outubro 2009

Serra Negra - SP

INTERACTION WITH


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


TECHNOLOGY TRANSFERTRANSFERÊNCIA DE CONHECIMENTO PARA O SETOR EMPRESARIAL

OU PARA O GOVERNO

GOVERNMENTAL POLICYPOLÍTICAS PÚBLICAS

Teacher training courses

via

State Department of Education


Medicinal Chemistry Centre for Chagas

Disease in Brazil

World Health Organization

~ 200 coumpounds

designed and

synthesized

~100 times improvement

on binding affinity of

benznidazol


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

http://ourofino.com/portal/institucional

INNOVATIONINOVAÇÕES

www.pkdb.ifsc.usp.br

INNOVATIONINOVAÇÕES

www.pkdb.ifsc.usp.br

Database: 1389 Compounds

Visits: 35,800

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

http://ourofino.com/portal/institucional

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

INTRODUCTION - Portal IFSC · Identificação de novos alvos moleculares 3 artigos....

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