HOW STUDYING HISTORY CAN AID DUG DISCOVERY - DRUG DEVELOPMENT FROM NATURAL PRODUCTS

Question 1

WHAT IS A ‘NATURAL PRODUCT’? (NP)

Answer 1

IN MEDICINAL CHEMISTRY (STRICT DEFINITION): A CHEMICAL COMPOUND OR SUBSTANCE MADE BY A LIVING ORGANISM THAT IS A SEOCNDARY COMPOUND (SOMETHING NOT ESSENTIAL FOR THE SURVIVAL OF THE ORGANISM, BUT SOMETHING ORGANISM PRODUCES IN RESPONSE TO ITS ENVIRONMENT) —> THIS DEFINITION USUALLY EXCLUDES PROTEINS AND REFERES TO ‘SMALL MOLECULES’, BUT SOME BROADER WORKING DEFINITIONS INCLUDE MIXTURES OF NPs AND MAY INCLUDE PROTEINS (DEFENCE PEPTIDES, ENZYMES) E.G. BOTANICAL WHOLE-PLANT EXTRACTS, HONEY

Question 2

HOW MANY DRUGS HAVE BEEN APPROVED FOR CLINICAL USE FROM 1981-2019? HOW MANY ARE SYNTHETIC PRODUCTS, HOW MANY VACCINES, HOW MANY NATURAL OR MIMICS OF/INSPIRED BY NATURAL PRODUCTS?

Answer 2

1881 DRUGS

• SYNTHETIC MOLECULES 24.6%
• VACCINES 7.5%
• REMAINING >60%: MIMIC OF NATURAL PRODUCT, UNLTERED NATURAL PRODUCT, SYNTHETIC MOLECULE INSPIRED BY NP, SYNTHETICALLY MODIFIED NP, BIOLOGICAL MCROMOLECULES, BOTANICAL PRODUCT

Question 3

‘BIOACTIVE’ MEANING?

Answer 3

( BIOLOGICALLY ACTIVE) HAVING AN EFFECT UPON A LIVING ORGANISM, TISSUE OR CELL
(ANTIBIOTICS, ENZYMES, AND VITAMINS ARE ALL BIOACTIVE SUBSTANCES)

Question 4

PACLITAXEL (TAXOL) DISCOVERY AND USE?

Answer 4

• IN THE 1960s THE US GOVERNMENT WERE FUNDING A PROGRAMME TO SCREEN PLANT EXTRACTS FOR ANTICANCER ACTIVITY
• ONE OF THE EXTRACTS THAT LOOKED PROMISING WAS FROM THE PACIFIC YEW TREE
• 2 SCIENTISTS WORKING ON THE PROJECT, DR MANSUKH WANI AND DR MONROE WALL, TESTED INDIVIDUAL MOLECULES FROM THIS EXTRACT AND FOUND THAT THE MOST CYTOTOXIC COMPOUND WAS PACLITAXEL (TAXOL)
• IT WORKS BY BLOCKING MITOSIS AND IS NOW USED IN CHEMOTHERAPY TO TREAT OVARIAN AND BREAST CANCER, WITH VERY GOOD RESULTS

Question 5

HOW WERE SOY BEANS USED TO MAKE SYNTHETIC HUMAN STEROID HORMONES? WHAT IMPACT DIDIT HAVE ON MEDICINE?

Answer 5

• DR PERRY JULIAN KNEW SOYBEANS (GLYCINE MAX) CAN MAKE A MOLECULE CALLED STIGMASTEROL - WHICH CAN BE USED AS A PRECURSOR TO A LOT OF HUMAN HORMONES, LIKE ESTROGEN, PROGESTERONE AND TESTOSTERONE
• INITIALLY, HIS ATTEMPTS MET WITH LIMITED SUCCESS BECAUSE HE COULDN’T EXTRACT STIGMASTEROL IN LARGE ENOUGH QUANTITIES
• A LUCKY ACCIDENT IN HIS LAB (A WATER LEAK) LEAD TO LARGE AMOUNTS OF WHITE SOLID SUBSTANCE TO FORM, AND HE REALISED IT WAS STIGMASTEROL AND STARTED EXTRACTING IT USING WATER
• HE WAS THEREFORE ABLE TO MAKE LARGE AMOUNTS OF HUMAN HORMONES VERY CHEAPLY
• BIGGEST IMPACT OF THIS WORK ON HUMAN HEALTH: IT WAS CRUCIAL FOR THE DEVELOPMENT OF THE CONTRACEPTIVE PILL AND OTHER HORMONE BASED CONTRACEPTIVES, AS WELL AS TREATMENTS FOR A VARIETY OF OTHER CONDITIONS

Question 6

ARTEMISININ DISCOVERY AND USE?

Answer 6

• 1960s: PROF TU YOUYOU LEAD A PROJECT FUNDED BY THE CHINESE GOVERNMENT TO FIND NEW TREATMENTS FOR DRUG RESISTANT MALARIA
• AT THIS POINT OVER 240 000 COMPOUNDS HAVE ALREADY BEEN TESTES FOR USE IN POTENTIAL ANTIMALARIAL DRUGS
• PROF TU AND HER TEAM TOOK A DIFFERENT APPROACH; FOCUSED ON PLANTS AND HERBS USED IN CHINESE HISTORICAL MEDICINE TO TREAT SYMPTOMS OF MALARIA
• SHE OBTAINED SOME PROMISING LAB RESULTS WITH EXTRACTS FROM SWEET WORMWOOD (ARTEMISIA ANNUA), BUT THEY DIDN’T LOOK POWERFUL ENOUGH TO BE CLINICAL;Y USEFUL
• HOWEVER, SHE WAS BOILING THE PLANT TO EXTRACT SUBSTANCES, WHILE TH ANCIENT TEXTS SAID TO PUT IT N COLD WATER
• SHE THEN TRIED COLD EXTRACTION AND IT WORKED —> THIS YIELDED ARTEMISININ, A VERY POTENT KILLER OF THE MALARIA PARASITE WHICH IS STILL USED AS AN ANTIMALARIAL DRUG —> SAVED MILLIONS OF LIVES
  (2015: PROF TU WON A NOBEL PRIZE FOR HER WORK)

Question 7

WHAT IS ETHNOPHARMACOLOGY?

Answer 7

THE SCIENTIFIC STUDY OF SUBSTANCES USED MEDICIANALLY BY DIFFERENT ETHNIC OR CULTURAL GROUPS (ESPECIALLY TRADITIONAL OR ‘FOLK’ REMEDIES)

Question 8

WHEN WAS THE LAST REGISTERED CLASS OF ANTIBIOTICS DISCOVERED?

Answer 8

1984

Question 9

THE 3 Rs PRINCIPLE?

Answer 9

REPLACE, REDUCE AND REFINE –> DESCRIBE THE MOST IMPORTANT ETHICAL PRINCIPLES IN EXPERIMENTAL SCIENTIFIC WORK WITH LABORATORY ANIMALS

REPLACE: AS MUCH AS POSSIBLE, REPLACE ANIMAL EXPERIMENTS WITH ALTERNATIVE METHODS + REPLACE MORE HIGHLY DEVELOPED ANIMALS BY LESS HIGHLY DEVELOPED AND THEREFORE LESS SUFFERABLE ANIMALS
REDUCE: ALL RESEARCHERS ENCOURAGED TO REDUCE ANIMAL TESTING AND AMOUNT OF ANIMALS USED TO A MINIMUM
REFINE: REFINE THE TEST METHODS IN SUCH A WAY THAT THE BURDEN ON THE ANIMALS IS REDUCED TO A MINIMUM (E.G. WITH ANAESTHETICS, NARCOTICS, PAINKILLERS), TRAIN THE ANIMAL TO GET USED TO EXPERIMENT CONDITIONS TO AVOID STRESS