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THE MADAGASCAR INTERNATIONAL COOPERATIVE BIODIVERSITY GROUP: BACKGROUND AND HISTORY. David Kingston Department of Chemistry Virginia Polytechnic Institute & State University Web: www .kingston.chem.vt.edu. Natural Products as Drugs and Drug Leads. 6%.

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THE MADAGASCAR INTERNATIONAL COOPERATIVE BIODIVERSITY GROUP: BACKGROUND AND HISTORY

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The madagascar international cooperative biodiversity group background and history l.jpg

THE MADAGASCAR INTERNATIONAL COOPERATIVE BIODIVERSITY GROUP: BACKGROUND AND HISTORY

David Kingston

Department of Chemistry

Virginia Polytechnic Institute & State University

Web: www .kingston.chem.vt.edu


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Natural Products as Drugs and Drug Leads

6%

  • WHO estimates that ~80% of the world’s population use traditional medicine.

  • Between 1983 and 1994 41% of new approved drugs had natural products as their source.

    David J. Newman, et al. Nat. Prod. Rep., 2000, 17, 215-234

    Gordon M. Cragg, et al. J. Nat. Prod., 1997, 60, 52-60

26%

59%

9%

  • Natural Product Drugs

  • Modified Natural Product Drugs

  • Synthetic Drugs Based on Natural Product Models

  • Synthetic Drugs


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MORE REASONS FOR FAITH IN NATURAL PRODUCTS

NP are more diverse than synthetics

Synthetic Compound from

combinatorial chemistry

Chiral ctr = 0.4

Natural Products

Chiral ctr = 6.2

Drugs

Chiral ctr = 2.3

Feher and Schmidt 2003 J

Chem Inf Comput Sci 43:218

61% of all the new drugs introduced Worldwide during 1981-2002 can be traced to or were inspired by Natural Products. Newman, Cragg, Snader 2003 J Nat Prod 66:1022


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SOME IMPORTANT ANTICANCER NATURAL PRODUCTS

TAXOL, from Taxus brevifolia

  • Treatment for ovarian and breast cancer

  • Also used in stents to prevent restenosis

  • Major drug, with sales of over one billion dollars/year


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WHY NATURAL PRODUCTS?

NATURAL PRODUCTS CAN FORM THE BASIS OF NEW COMPOUND LIBRARIES

R. Breinbauer et al, Angew. Chem. Int. Ed. 2002, 41, 2878

EXAMPLE: THE HALICHONDRINS

M. J. Yu 224th ACS National Meeting, Boston, MA, August 21, 2001, Abstract MEDI 238.


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DRUG DISCOVERY THROUGH NATURAL PRODUCTS

COLLECT LARGE NUMBERS OF PLANT, MARINE, OR MICROBIAL SPECIES

PREPARE EXTRACTS AND TEST IN RELEVANT BIOASSAY SYSTEMS

RECOLLECT OR REFERMENT ACTIVE SPECIES AND ISOLATE ACTIVE COMPOUNDS BY A BIOASSAY-DIRECTED FRACTIONATION

DETERMINE STRUCTURES OF BIOACTIVE COMPOUNDS

CARRY OUT ADDITIONAL BIOLOGICAL TESTING


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THE PROBLEM OF BIODIVERSITY LOSS

DRUG DISCOVERY REQUIRES RANDOM SCREENING OF THOUSANDS OF SPECIES “YOU HAVE TO KISS A LOT OF FROGS TO FIND A PRINCE”

TROPICAL RAINFORESTS COVER ONLY 8% OF THE EARTH’S SURFACE BUT HOLD 50% OF ITS PLANTS

TROPICAL FORESTS ARE DISAPPEARING FAST; DOWN FROM 16% OF EARTH’S LAND SURFACE IN 1950 TO LESS THAN 8% TODAY

TROPICAL REEFS ARE ALSO UNDER THREAT

LOSS OF RAINFOREST MEANS THE POTENTIAL LOSS OF CURES FOR CANCER, AIDS, ETC.


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Brazil Vegetation 1960


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Brazil Brazil Vegetation 1988


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THE MADAGASCAR ICBG APPROACH TO BIODIVERSITY CONSERVATION

CARRY OUT BIOPROSPECTING WITH FULL INFORMED CONSENT OF ALL PARTIES

PARTNER WITH PHARMACEUTICAL AND AGROCHEMICAL COMPANIES

SINCE BIODIVERSITY LOSS IS CLOSELY ASSOCIATED WITH POVERTY, COMBINE BIOPROSPECTING WITH ECONOMIC DEVELOPMENT ACTIVITIES

COMMIT TO RETURN ANY ROYALTY PAYMENTS IN PART TO THE HOST COUNTRY IN COMPENSATION FOR USE OF ITS BIODIVERSITY


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HOW AND WHERE TO DO THIS?

  • 1992 NATIONAL INSTITUTES OF HEALTH INVITED SCIENTISTS TO COMPETE FOR FUNDS TO DO DRUG DISCOVERY AND BIODIVERSITY CONSERVATION

  • 1993-1998 VIRGINIA TECH PROPOSAL FUNDED TO DO WORK IN SURINAME

  • 1998-2003 RENEWAL PROPOSAL FUNDED TO DO WORK IN SURINAME AND MADAGASCAR

  • 2003-2008 THIRD ROUND OF FUNDING AWARDED FOR WORK IN MADAGASCAR


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MADAGASCAR GROUP STRUCTURE

  • VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY

    • CENTRAL OPERATIONS OFFICE

  • MISSOURI BOTANICAL GARDEN

    • BOTANICAL COLLECTIONS, BIODIVERSITY SURVEY

  • CONSERVATION INTERNATIONAL

    • ECONOMIC DEVELOPMENT, BIODIVERSITY CONSERVATION

      CENTRE NATIONAL D’APPLICATION ET DES RECHERCHES PHARMACEUTIQUES

    • PLANT EXTRACTS, ANTIMALARIAL FRACTIONATION

      CENTRE NATIONAL DE RECHERCHES SUR L’ENVIRONNEMENT

    • MARINE COLLECTION, MICROBIAL ISOLATIONS

      EISAI RESEARCH INSTITUTE

    • BIOASSAY, DRUG DISCOVERY AND DEVELOPMENT

  • DOW AGROSCIENCES

    • AGROCHEMICAL DISCOVERY AND DEVELOPMENT

  • VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY

    • BIOASSAY AND ANTICANCER DRUG DISCOVERY


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GOALS OF THE MADAGASCAR ICBG PROGRAM

TO INTEGRATE THE PROCESS OF DRUG AND AGROCHEMICAL DISCOVERY FROM NATURAL PRODUCTS WITH CONSERVATION OF BIODIVERSITY AND SUSTAINABLE ECONOMIC DEVELOPMENT, WHILE PROVIDING FINANCIAL BENEFITS TO MADAGASCAR AND ITS PEOPLE


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WHY MADAGASCAR?

  • Madagascar is a prime

    source of biodiversity.

  • Madagascar is one of

    the highest priority

    “Biodiversity Hotspots”

  • Home to 25% of the plant

    species in the African region

  • Approximately 80% of species

    are endemic

  • Great ecosystem diversity

  • Work is urgent, since much of the country has been deforested

MADAGASCAR


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SCIENTIFIC DEVELOPMENT IN MADAGASCAR

  • Laboratories at CNARP have been equipped to prepare plant extracts

  • Laboratories at CNARP have been equipped and personnel trained to carry out antimalarial bioassays

  • Facilities at CNRO (Nosy be) are being equipped to carry out marine collections

  • Personnel at CNRE will be trained in microbial isolations

  • Data handling infrastructure has been expanded


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ECONOMIC DEVELOPMENT IN MADAGASCAR

  • SMALL-SCALE ECONOMIC DEVELOPMENT PROJECTS IN THE VILLAGES AROUND ZAHAMENA PARK, SITE OF 1998-2003 COLLECTIONS

    BEE KEEPING

    ECOTOURISM INITIATIVE

    IMPROVED CROPS


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ECONOMIC DEVELOPMENT IN MADAGASCAR

  • SMALL-SCALE ECONOMIC DEVELOPMENT PROJECTS IN THE VILLAGES AROUND ZAHAMENA PARK, SITE OF 1998-2003 COLLECTIONS

    BEE KEEPING

    ECOTOURISM INITIATIVE

    IMPROVED CROPS

  • INFRASTRUCTURE IMPROVEMENTS USING UPFRONT COMPENSATION FUNDS IN THE SAME VILLAGES

    AGRICULTURAL WAREHOUSE

    RENOVATION OF A PRIMARY SCHOOL

    CONSTRUCTION OF A FOOTBRIDGE


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