Department of ChemistryPondicherry UniversityPondicherry - 605 014

Email: hspr.che@pondiuni.edu.inWebsite: www.pondiuni.edu.in

The Nobel Prize in Physiology or Medicine 2015

a lecture by

Dr. H. Surya Prakash Rao

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Youyou TuPrize share: 1/2

The Nobel Prize in Physiology or Medicine 2015

William C. CampbellPrize share: 1/4

Satoshi ŌmuraPrize share: 1/4

One half jointly to William C. Campbell and Satoshi Ōmura “for theirdiscoveries concerning a novel therapy against infections caused byroundworm parasites" and the other half to Youyou Tu "for herdiscoveries concerning a novel therapy against Malaria".

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2015/2

Facts on the Nobel Prize in Physiology or Medicine

http://www.nobelprize.org/nobel_prizes/facts/medicine/index.html

On 27 November 1895, Alfred Nobel signed his last will and testament : The income from the investments was to be "distributed annually in the form of prizes to those who during the preceding year have conferred the greatest benefit to mankind."

One part was dedicated to "the person who shall have made the most important discovery within the domain of physiology or medicine“ to be awarded by by the Carolinska Institute in Stockholm (about 50 members).

106 Nobel Prizes (210 individuals) in Physiology or Medicine have been awarded since 1901. It was not awarded on nine occasions: in 1915, 1916, 1917, 1918, 1921, 1925, 1940, 1941 and 1942.

38 - one Laureate; 32 two Laureates; 36 three Laureates. – 12 women (including that of Tu)

The Nobel Prize amount for 2015 is set at Swedish kronor (SEK) 8.0 million (SEK80,00,000 x @7.85 = Rs. 6,27,88,370.00) per full Nobel Prize

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The Nobel Prize in Physiology or Medicine 2015

http://www.nobelprize.org/nobel_prizes/medicine

October 5, 2015Announcement: Professor Juleen Zierath, Chair of the Nobel Committee for Physiology or Medicine http://www.nobelprize.org/mediaplayer/index.php?id=2563

The 2015 Nobel Prize in Physiology or Medicine was awarded for discoveries in novel therapies for some of the most devastating parasitic diseases: River Blindness, Lymphatic Filariasis (Elephantiasis) and Malaria. The distribution of these diseases is quite similar and is collectively shown in blue on the world map above

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Malaria

http://www.who.int/mediacentre/factsheets/fs094/en/

Malaria is known from time immemorial – Hippocrates noted it as tropical disease►Thomas Sydenham described symptoms in 1680►Sir Ronold Ross (British Bacteriologist working in India – role of mosquito vector; Nobel Prize 1902►Camilo Golgi (Italian physiologist – structure of nervous system Nobel Prize 1906►Charles Louis Alhonse Laveran (French doctor) role of the parasite; Nobel Prize 1907►Julius Wagner-Jauregg – Nobel Prize 1927 for discovering inoculation for malaria - immune development – did not work on sustainable basis►Paul Herman Miller (Swiss Chemist; inventor of DDT; Nobel Prize 1948 – later discoveries showed that DDT is a major cause for pollution – banned substance in many countries.

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Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female mosquitoes. About 3.2 billion people – almost half of the world’s population – are at risk of malaria. However, globally between 2000 and 2015, malaria incidence (the rate of new cases; better living) fell by 37% and cases of death fell by 60% among all age groups (better health care).Sub-Saharan Africa carries a disproportionately high share of the global malaria burden. In 2015, the region was home to 89% of malaria cases and 91% of malaria deaths.

Malaria

http://www.who.int/mediacentre/factsheets/fs094/en/ 6

Anopheles mosquitoes, called "malaria vectors.” P. falciparum (in Africa) and P. vivax (Asia) (out of five species) are more prevalent. These parasites enter red blood cells, feed upon the protein therein and destroys them. Plasmodium is transferred from an infected person to a healthy individual by the females of several species of Anopheles mosquitoes, which use human blood as a means to provide nourishment for their developing eggs.

Malaria

http://www.who.int/mediacentre/factsheets/fs094/en/ 7

Malarial parasite – life cycleP. falciparum, P. vivax, P. ovale and P. malariae

(1) Hepatocytes (in liver)(2-4) Exoerythrocytic schizogony (asexual reproduction within hepatocyces)(5) Resulting merozoites are released into blood stream some stay dormant - hypnozoites - months to years - relapse(6) Merozoites invade erythrocytees(7-8) parasite enlarges - ring form - trophozoite - proteolysis of hemoglobin into amino acids(9) Nuclear division to result in schizont(10) Merozoites bud from mature schizont called segmenter(11) Merozoites are released following rupture of infected erythrocyte; Invasion of erythrocytes reinitiates another round (intermittent fever)(12) Sexual form differentiation (alternative to asexual reproduction) - macro and microgametocytes - lowering of temperature(13) Exflagellation(14) Fertilization(15) Zygote formation(16) Zygote develops into ookinete(17) Ookinete penetrates the gut epithelial cells and develops into Oocyst(18) Oocyst reproduction(19) production of sporozoites in mosquito(20) move into body cavity of mosquito

http://www.tulane.edu/~wiser/malaria/mal_lc.PDF

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This 1970 first day cover commemorates the 150th anniversary of Pelletier and Caventou's isolation of quinine.

The Quest for Quinine: Those Who Won the Battles and Those Who Won the WarKaufman, T. S.; Rfflveda, E. A., Angew. Chem. Int. Ed. 2005, 44, 854 – 88

Quinine

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Quinine

This fortuitous discovery of anti-malarial properties of cinchona bark seems to have taken place while the Count of Chinchon was Viceroy of this part of the Spanish colonies;His wife, the Countess of Chinchon, was miraculously cured from malaria after being treated with a remedy made from cinchona bark specially brought to Lima from Loxa (now Loja, Ecuador) – Cinchona tree was named of the countess with a spelling mistake.

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Wilhelm von Hofmann – Royal College, London took challenge to synthesize quinine from coal-tar products

Quinine

William Perkin – student of Hofmann – 1856 - 18 years set to synthesize quinine12

Quinine – related antimalarials

Patrick, G. L. Introduction to Medicinal Chemistry, 2013 13

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Quinine – related antimalarials

Parthiban, A.; Muthukumaran, J.; Krishna, R.; Rao, H. S. P. Bioorg. Med. Chem. Lett. 2015, 00015

Artemisinin – Youyou Tu (Chinese Pharmacologist )

2011, Lasker Award, in New York1951 with her teacher Lou Zhicen

Tu Youyou is a Chinese medical scientist, pharmaceutical chemist, pharmacist and educatorBorn: December 30, 1930 (age 84), Ningbo, ChinaEducation: Pharmacy Department at Beijing Medical University in 1955; China Academy of Traditional Chinese Medicine: 1965-1978 Assistant Professor;1979-1984 Associate Professor; 1984-2000 – Full professor; 2000- to present Chief Professor

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Endoperoxide based Anti-malarial drugs

From leaves of Artemisia annua – Chinese herb; aka Qinghaosu

Cultural revolutionWar in Vietnam (Ho Chi Minh, Zhou En-Lai, Mao Tse-Tung) Indigenous search Screening of over 2000; travel to interior China Cold extraction Animal, primate and self-ingestion Publications in Chinese journals and treatment Revelation to world in 1979

7 asymmetric centers

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Biosynthesis of Artemisinin

Paddon, C. J.; Keasling, J. D. Nature Reviews Microbiology, 2014, 12, 355–367.18

Structural Modification of Artemisinin

19Patrick, G. L. Introduction to Medicinal Chemistry, 2013

Mechanism of action of artemisinin

Krishna, S.; Uhlemanna, A-C.; Haynes, R. K. Drug Resistance Updates 2204, 7, 233–244.

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Analogs and related molecules of artemesinin

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Synthetic analogs of artemesinin

Chaudhary, S.; Sharma, V.; Jaiswal, P. K.; Gaikwad, A. N.; Sinha, S. K.; Puri, S K.; Sharon, A; Maulik, P. R.; Chaturvedi, V. Org. Lett., 2015, 17, 4948–495

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William C. Campbell

William C. Campbell was born in 1930 in Ramelton, Ireland. Afterreceiving a BA from Trinity College, University of Dublin, Ireland in 1952,he received a PhD from University of Wisconsin, Madison, WI, USA in1957. From 1957-1990 he was with the Merck Institute for TherapeuticResearch, from 1984-1990 as Senior Scientist and Director for AssayResearch and Development. Campbell is currently a Research FellowEmeritus at Drew University, Madison, New Jersey, USA.

23http://www.nobelprize.org/nobel_prizes/medicine/laureates/2015/

Satoshi Ōmura was born in 1935 in the Yamanashi Prefecture, Japan and is a Japanese Citizen. He received a PhD in Pharmaceutical Sciences in 1968 from University of Tokyo, Japan and a PhD in Chemistry in 1970 from Tokyo University of Science. He was a researcher at the KitasatoInstitute, Japan from 1965-1971 and Professor at Kitasato University, Japan from 1975-2007. From 2007, Satoshi Ōmura has been Professor Emeritus at KitasatoUniversity.

Satoshi Ōmura

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Therapy against infections caused by nematode parasites

Medicines for bacterial infectionsGerhard Domagk - sulfonamides (Nobel Prize 1939); Alexander Fleming, Ernst Chain and Howard Flory - Penicillins (Nobel Prize 1945). Selman Waksman – streptomycin (Nobel Prize 1952).

Medicines for nematode infections (human or live-stock)Not much!

River BlindnessOnchocerciasis or African River Blindness is caused by the filarial worm Onchocercavolvulus. Affects populations close to rivers – so name. Flies stay close to rivers.Female black-fly (vector) bite O. volvolus filarial larvae (third stage) enter bottom of skin through bite wound. They mature (up to 18 cm; 0.2-04 mm) and infect body including eyes. Progressive blindness. Sub-Saharan Africa, south Asia, and South and Central America – 250 million by 2016

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Lymphatic Filariasis elephantiasis; more than 120 millionpeople) Filariodidea (Wuchereriabancrofti; Brugia malayi; Brugia timor)Mosquitoes are intermediate hosts; 30-40 mm length and 02-03 mm thick. Live 5-7 years in lymph nodes. damaged and dilated lymphatic vessels cause blockages, swelling of the limbs, fever and immobilization

Therapy against infections caused by nematode parasites

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Satoshi Ōmura searched for novel strains of Streptomyces bacteria as a source for new bioactivecompounds. He isolated microbes from soil samples in Japan, cultured them in the laboratory (inset to left) and characterized many thousands of Streptomyces cultures. From those, he selected ~50 cultures that appeared most promising, and one of these cultures later turned out to be Streptomyces avermitilis, the source of Avermectin.

Search for Avermectin

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Structure of Avermectin and Ivermectin

Ivermectin treatment is highly effective because it only needs to be taken once or twice a year, needs no refrigeration, and has a wide margin of safety, with the result that it has been widely given by minimally trained community health workersIvermectin kills the parasite by interfering with the nervous system and muscle function, in particular, by enhancing inhibitory neurotransmission. The drug binds to and activates glutamate-gated chloride channels. These channels, present in neurons and myocytes, are not invertebrate-specific, but are protected invertebrates from the action of ivermectin by the blood–brain barrier

Satoshi Ōmura is trained as a microbiologist with expertise in isolating natural products.William C. Campbell is an expert in parasite biology

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(1) extraordinarily potent; (2) active against many intestinal nematodes in various host species; (3) showing durable long-term activity against some extra intestinal parasites including blood-dwelling filarial microfilariae;(4) Even active against benzimidazole-resistant nematodes(5) well-tolerated by the host species, therefore a good margin of safety(6) Jimmy Carter (former President of USA and Nobel Peace Prize laureate 2002) foundation helped distribution of ivarimectin.

Advantages of Ivermectin

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Thank you

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