Vincent Du Vigneaud Research Articles

The Long Way of Oxytocin from the Uterus to the Heart in 70 Years from Its Discovery.

The research program on oxytocin started in 1895, when Oliver and Schafer reported that a substance extracted from the pituitary gland elevates blood pressure when injected intravenously into dogs. Dale later reported that a neurohypophysial substance triggers uterine contraction, lactation, and antidiuresis. Purification of this pituitary gland extracts revealed that the vasopressor and antidiuretic activity could be attributed to vasopressin, while uterotonic and lactation activity could be attributed to oxytocin. In 1950, the amino-acid sequences of vasopressin and oxytocin were determined and chemically synthesized. Vasopressin (CYFQNCPRG-NH2) and oxytocin (CYIQNCPLG-NH2) differ by two amino acids and have a disulfide bridge between the cysteine residues at position one and six conserved in all vasopressin/oxytocin-type peptides. This characterization of oxytocin led to the Nobel Prize awarded in 1955 to Vincent du Vigneaud. Nevertheless, it was only 50 years later when the evidence that mice depleted of oxytocin or its receptor develop late-onset obesity and metabolic syndrome established that oxytocin regulates energy and metabolism. Oxytocin is anorexigenic and regulates the lean/fat mass composition in skeletal muscle. Oxytocin's effect on muscle is mediated by thermogenesis via a pathway initiated in the myocardium. Oxytocin involvement in thermogenesis and muscle contraction is linked to Prader-Willi syndrome in humans, opening exciting therapeutic avenues.

60 YEARS OF POMC: Lipotropin and beta-endorphin: a perspective.

Many important fields of research had a humble origin. In the distant past, A J P Martin's discovery that amino acids could be separated by paper chromatography and Moore and Stein's use of columns for quantitative amino acid analysis provided the first steps towards the determination of structure in complex biologically active molecules. They opened the door to reveal the essential relationship that exists between structure and function. In molecular endocrinology, for example, striking advances have been made by chemists with their expertise in the identification of structure working with biologists who contributed valuable knowledge and experience. Advantage was gained from the convergence of different background, and it is notable that the whole is greater than the sum. In the determination of structure, it may be recalled that four of the world's great pioneers (Archibald Martin, Rodney Porter, Fred Sanger and Vincent du Vigneaud) were acknowledged for their fundamental contributions when individually they were awarded the Nobel Prize. They foresaw that the identification of structure would prove of outstanding importance in the future. Indeed, study of the structures of β-endorphin and enkephalin and the different forms of opiate activity they engender has led to a transformation in our understanding of chemical transmission in the brain.

Vincent du Vigneaud: following the sulfur trail to the discovery of the hormones of the posterior pituitary gland at Cornell Medical College.

In 1955, Vincent du Vigneaud (1901-1978), the chairman of the Department of Biochemistry at Cornell University Medical College, was awarded the Nobel Prize for Chemistry for his research on insulin and for the first synthesis of the posterior pituitary hormones-oxytocin and vasopressin. His tremendous contribution to organic chemistry, which began as an interest in sulfur-containing compounds, paved the way for a better understanding of the pituitary gland and for the development of diagnostic and therapeutic tools for diseases of the pituitary. His seminal research continues to impact neurologists, endocrinologists, and neurosurgeons, and enables them to treat patients who had no alternatives prior to du Vigneaud's breakthroughs in peptide structure and synthesis. The ability of neurosurgeons to aggressively operate on parasellar pathology was directly impacted and related to the ability to replace these hormones after surgery. The authors review the life and career of Vincent du Vigneaud, his groundbreaking discoveries, and his legacy of the understanding and treatment of the pituitary gland in health and disease.

Lester Reed: A “complex” man who loved science

Lester J. Reed, a pioneer in the field of biochemistry, died peacefully in Austin, Texas on January 14, 2015 at the age of 90. Lester Reed was born in New Orleans on January 3, 1925. He showed an early interest in chemistry, having his own laboratory in a shed under his boyhood home. He received his Bachelors of Science from Tulane in 1943, where he worked with William Shive, and earned his doctorate from the University of Illinois in 1946, where he worked with Reynold Fuson. Lester was 21 when he earned his doctorate. He then moved to Cornell University Medical School for a two-year postdoctorate in the laboratory of Vincent du Vigneaud. Two momentous events occurred during this short period: Lester was introduced to the field of biochemistry, and he met and married the love of his life, Janet Gruschow. In 1948, at age 23, Lester was recruited to the Chemistry Department at the University of Texas at Austin by Shive, who had moved there from Tulane. He joined a team led by Roger Williams studying vitamins. Lester isolated and identified the “acetate-replacing factor,” first observed by Esmond Snell, as lipoic acid. Later, working in collaboration with Eli Lilly and Co., they were able to purify about 30 mg of lipoic acid from over 10 tons of liver tissue!

Shedding Heat on Oxytocin

More than a century ago, Sir Henry Dale demonstrated that a component of the pituitary causes contractions of the mammalian uterus (1), hence his coining the term “oxytocic,” derived from the Greek for “quick birth,” for its activity. The discovery that a component of the pituitary causes milk secretion followed within a few years (2, 3). By 1930, oxytocin (OXT) was separated from vasopressin into pitocin and pitressin, respectively, at Parke Davis and made available for research (4). That a single peptide was responsible for these uterine and mammary actions was definitively confirmed upon the sequencing and synthesis of the peptide, 9 amino acids in length (5). Vincent du Vigneaud was awarded a Nobel Prize for this work. The cloning and sequencing of the rat OXT gene 30 years later (6), followed by cloning of the single OXT receptor (OXTR) (7), enabled the tremendous contributions of molecular biology, including studies on the regulation of the genes' expression and the creation of OXT (8, 9) and OXTR (10, 11) gene knockouts (KOs; below).

Congratulations to our award winners

It is with pleasure to recognize Victor Hruby in this issue of Biopolymers Peptide Science. Victor received the Murray Goodman Award for Scientific Excellence and Mentorship. This award recognizes individuals who have demonstrated career-long research excellence in the field of peptide science, while demonstrating significant mentorship and training of students, post-doctoral fellows and co-workers. Victor is undoubtedly one of the giants in peptide science and his scientific contributions are many. However, equally impressive is his commitment to mentorship. Victor has trained over 90 postdoctoral fellows, 65 graduate students, and 20 Masters students spanning a career of over 40 years. In this issue, Victor provides a personal glimpse into his own research career and shares his philosophy of Mentorship. He offers encouraging and helpful words especially poignant for young scientists staring their careers. In addition to Victor's accomplishments, I would also like to recognize the recently announced American Peptide Society award winners. These awards will be presented at the 23rd APS symposium in Hawaii this June. James Tam from the Nanyang Technological University will receive the Bruce Merrifield Award. The Merrifield Award recognizes lifetime achievement in peptide science at the highest level of scientific creativity. Sam Gellman, from the University of Wisconsin-Madison, has won the Makineni Award. This award recognizes original and singular discoveries rather than lifetime contributions. The 2013 Vincent du Vigneaud Awards will be presented to Michael Chorev, Harvard Medical School, and Kit Lam, UC-Davis. The Vincent du Vigneaud Award recognizes outstanding achievements in peptide research. Congratulations to all, Joel Schneider Editor-in-Chief

Impact of the Merrifield solid phase method on the design and synthesis of selective agonists and antagonists of oxytocin and vasopressin: A historical perspective

This tribute to Bruce Merrifield traces the author's fortuitous path in 1964 from Vincent du Vigneaud's laboratory to the laboratory of D. W. Woolley to learn the solid phase method and then to his first faculty position in the Department of Biochemistry, McGill University, Montreal in 1965. It recalls the key roles played from early 1966 to July 1967 by Bruce Merrifield, John Stewart, Arnold Marglin, Herb Takashima, and Vincent du Vigneaud in providing key advice to the author's efforts to use the solid phase method to synthesize oxytocin; while simultaneously the du Vigneaud and Merrifield laboratories were collaborating on the solid phase synthesis of deamino-oxytocin. Both syntheses were published in the same issue of the Journal of American Chemical Society in 1968. Also described is how this breakthrough impacted the author's scientific career: by leading to highly productive collaborative studies, initially with Wilbur H. Sawyer and subsequently with others, on the design and synthesis of selective agonists, antagonists, and radioiodinated ligands for oxytocin and vasopressin receptors. These syntheses were greatly facilitated by the contributions of highly talented graduate students, research technicians, and visiting peptide chemists from Hungary, England, Poland, Bulgaria, and China. Many of these peptides have become very valuable pharmacological tools in studies on the peripheral and central effects of oxytocin and vasopressin: further attesting to the profound impact of the solid phase method as the cornerstone for all the discoveries, which he and his collaborators and coworkers have made over the past 40 years.

The Nobel trail of Vincent du Vigneaud

The Nobel Prize for chemistry of 1955 was awarded to Vincent du Vigneaud. After a brief outline of his career and accomplishments, some archive material related to this decision of the Royal Swedish Academy of Sciences is presented. Other archive studies have shown that du Vigneaud was also considered for the corresponding prize in physiology or medicine.

Polio and nobel prizes: Looking back 50 years

In 1954, John Enders, Thomas Weller, and Frederick Robbins were awarded the Nobel Prize in Physiology or Medicine "for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue."5370 This discovery provided for the first time opportunities to produce both inactivated and live polio vaccines. By searching previously sealed Nobel Committee archives, we were able to review the deliberations that led to the award. It appears that Sven Gard, who was Professor of Virus Research at the Karolinska Institute and an adjunct member of the Nobel Committee at the time, played a major role in the events leading to the awarding of the Prize. It appears that Gard persuaded the College of Teachers at the Institute to decide not to follow the recommendation by their Nobel Committee to give the Prize to Vincent du Vigneaud. Another peculiar feature of the 1954 Prize is that Weller and Robbins were included based on only two nominations submitted for the first time that year. In his speech at the Nobel Prize ceremony, Gard mentioned the importance of the discovery for the future production of vaccines, but emphasized the implications of this work for growing many different, medically important viruses. We can only speculate on why later nominations highlighting the contributions of scientists such as Jonas Salk, Hilary Koprowski, and Albert Sabin in the development of poliovirus vaccines have not been recognized by a Nobel Prize.

The Role of the Merrifield Solid Phase Method in the Discovery and Exploration of a New Class of Selective Vasopressin Hypotensive Agonists

The Merrifield solid phase method (MSPM) has been of inestimable value in studies aimed at the design of selective agonists and antagonists of the V1a (vascular), V1b (pituitary), V2 (renal) and OT (uterine) receptors for vasopressin (VP) and oxytocin (OT). Here we describe how, 40 years after the landmark syntheses of oxytocin and vasopressin by Vincent du Vigneaud and colleagues, it led to the discovery of a new class of vasopressin agonists which exhibit selective hypotensive activity. We also point to the role of serendipity in this discovery. We furthermore show how the MSPM has been of inestimable value in facilitating a rapid and comprehensive structure activity study of the lead hypotensive peptide: d(CH2)5[D-Tyr(Et)2,Arg3,Val4]AVP (A) giving rise to d(CH2)5[D-Tyr(Pri)2,Arg3,Val4,Lys7,Eda9]LVP (B) which exhibits a 30-fold enhancement in vasodepressor potency relative to (A). Here, we also report a structure activity study of (B) with single modifications at position 3 (Lys, Nar) and 4 (Cha, Nle, Leu, Abu, Nva, Thr, Har) and combined modifications at positions 3 and 9 (Nar and EdaG) and 7 and 9 (Arg and Eda ← retro Tyr). All modifications of (B) are well tolerated with good retention of vasodepressor potency. These findings offer promising clues to the design of more potent VP hypotensive agonists and of critically needed antagonists of the putative VP vasodilating receptor. The Merrifield Solid Phase Method will continue to play a pivotal role in these studies.

Editorial

The papers in this issue of Peptide Science reflect the scientific identity of the journal, as well as the truly international character of the field of peptide chemistry and biology. We are very pleased to present a review solicited from one of the recipients of the 2004 Vincent du Vigneaud Awards from the American Peptide Society. Dieter Seebach of the ETH, Zurich, was honored for “the discovery of peptides consisting of homologated proteinogenic amino acids and of their unexpected chemical, structural, and biological properties.” His review in this issue provides an extensive discussion of β-amino acids, specifically those with side chains in the carbonyl position, including their occurrence in nature, their synthesis, and their uses in design of novel peptide properties. We congratulate Dieter for this richly deserved recognition, and we thank him for providing an exciting review to Peptide Science. The original papers appearing in this issue epitomize the field of peptide science and illustrate the power of peptide synthesis and conformational study: Chakrabarty and coworkers present results of peptide design aimed at deducing the principles for helical bundle formation. Their work explores factors important in packing of α-helices and shows how peptide studies can shed light on fundamental ‘rules’ for the formation of protein architectures. The use of synthetic peptides to elucidate the origins of biological activity is the theme of the paper contributed by Epand and coworkers, who are exploring how the biological activity of calcitonin analogues correlates with their biophysical properties. Lastly, Alix and coworkers present synergistic experimental and computational studies of the conformational preferences of short peptides responsible for the elasticity of elastin, a major component of the extracellular matrix.

Announcements 2002 Vincent duVigneaud Award: American Peptide Society Request for Nominations

The Journal of Peptide ResearchVolume 58, Issue 5 p. 442-442 Announcements2002 Vincent duVigneaud Award: American Peptide Society Request for Nominations First published: 09 October 2008 https://doi.org/10.1034/j.1399-3011.2001.058005442.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume58, Issue5November 2001Pages 442-442 RelatedInformation

2002 Vincent duVigneaud Award: American Peptide Society Request for Nominations

The Journal of Peptide ResearchVolume 58, Issue 3 p. 274-274 2002 Vincent duVigneaud Award: American Peptide Society Request for Nominations First published: 09 October 2008 https://doi.org/10.1034/j.1399-3011.2001.058003274.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume58, Issue3September 2001Pages 274-274 RelatedInformation

Vincent duVigneaud 1901-1978: a personal tribute.

The Journal of Peptide ResearchVolume 58, Issue 3 p. 191-192 Vincent duVigneaud 1901–1978: a personal tribute Victor J. Hruby, Victor J. Hruby Editor-in-ChiefSearch for more papers by this author Victor J. Hruby, Victor J. Hruby Editor-in-ChiefSearch for more papers by this author First published: 08 December 2008 https://doi.org/10.1034/j.1399-3011.2001.00583.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume58, Issue3September 2001Pages 191-192 RelatedInformation

Vasopressin receptors: structural functional relationships and role in neural and endocrine regulation.

Vasopressin (VP) is the biologically active peptide whose endocrine and neural actions, chemical structure, biosynthesis and receptors were described before any other peptide hormone. In this respect, VP has fulfilled an important role as a prototype peptide in the fields of endocrinology and neurosciences, and has always been on the brink of novel advances and concepts. VP was described originally as an entity in posterior pituitary extracts that led to antidiuresis and vasoconstriction, hence its name. In the 1950s it was purified from this gland and its chemical structure determined, an achievement by Vincent du Vigneaud that was honored by the Nobel prize in 1955 (Du Vigneaud 1956). It turned out to be a nonapeptide with an internal disulfide bridge and amidated C terminus, Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-G1yNH2, and to be closely related to oxytocin (OT). VP has been the leading component in the concepts of neurosecretion and neuropeptides (Bargmann 1966; De Wied 1997). The VP/OT signaling system is evolutionarily old as is illustrated by the presence of highly similar peptides and receptors in diverse metazoans such as mollusca, arthropoda, annelida and chordata.

James A. Wells of Genentech and Peter W. Schiller of the Clinical Research Institute of Montreal Receive Vincent du Vigneaud Awards of the American Peptide Society

James A. Wells of Genentech and Peter W. Schiller of the Clinical Research Institute of Montreal Receive Vincent du Vigneaud Awards of the American Peptide Society

Synthetic analogs of oxytocin and the vasopressins.

Vincent du Vigneaud and his associates synthesized oxytocin and the vaso­ pressins almost twenty years ago. These were the first polypeptide hormones prepared by total synthesis. Their pharmacological properties were identical with those of the purified natural hormones. This provided elegant proof that the molecular structures determined by previous analyses were indeed correct. Once the structures of the mammalian neurohypophysial hormones were established several groups began preparing synthetic analogs. These were not synthesized at random, but with several general purposes in mind. These included: (a) Definition of the importance of specific molecular structures to the varied

Vincent duVigneaud—The Man

VINCENT DU VIGNEAUD is at 44 an outstanding American scientist and leader, by virtue both of perspective and of technical competence in biological chemistry and in the medical sciences. In honoring him we honor the achievements of American science. It behooves us therefore to study carefully the training and the welding together of different disciplines which have developed the man and enabled him to inspire his students, both his research chemists and his medical students, and through them directly, to influence his time. Born in Chicago, Ill., on May 18, 1901 he went to the University of Illinois in 1918. There he found the teachers, the training, and his own orientation toward the diverse scientific disciplines to which he was exposed. His best grades were in mathematics, and he was interested in physical chemistry, but organic chemistry was his major, although he already knew that his interest was in biological ...

Isolation of a Heavy Sulphur

AT the hundredth meeting of the American Chemical Society, which opened at Detroit on September 9, Drs. David W. Stewart and Karl Cohen, of Columbia University, described the preparation of heavy sulphur. According to Science Service, of Washington, D.C., the researches were conducted under the direction of Prof. Harold C. Urey, head of the Department of Chemistry of the University, who received the Nobel prize for chemistry in 1934 for his work in the discovery of heavy hydrogen. Ordinary sulphur contains four isotopes; S32 (95 per cent); S34 (4 per cent), which is the isotope now isolated; S33 (1 per cent); and S36 (O˙Ol per cent). Separation of the isotope was achieved with Prof. Urey's counter-current scrubbing method, previously used to separate isotopes of carbon and of nitrogen. Sulphur dioxide was passed up through 150 ft. of sodium hydrogen sulphite flowing downwards. S34 is more soluble in the liquid than the other varieties; and, at the end of the proeess, the emergent liquid contained about a quarter of the heavy isotope. Researches are now being carried out by Dr. Vincent du Vigneaud, professor of biochemistry in the Cornell University School of Medicine, using heavy sulphur to determine the role of the element in the chemistry of the living organism.

Administration of Ascorbic Acid to an Alkaptonuric Patient.

SummaryThe administration of from 1 to 4 g of ascorbic acid per day has been found to be without effect on the excretion of homogentisic acid by an alkaptonuric individual excreting an average of 7 g of the metabolite daily. The ineffectiveness of this excessive amount of vitamin is a rinding which is in agreement with results with smaller doses obtained by other investigators.The authors are indebted to Professor Vincent du Vigneaud for placing at their disposal laboratory facilities in the Department of Biochemistry of the Cornell University Medical College for the chemical work in connection with this experiment, and to Dr. Elaine P. Ralli of the Department of Medicine of New York University for the determination of the blood ascorbic acid.