Eli Lilly Award in Biological Chemistry

Professor Brad Pentelute, Massachusetts Institute of Technology

For outstanding research in biological chemistry of unusual merit and independence of thought and originality.

 

Professor Brad Pentelute is the recipient of the 2018 Eli Lilly Award in Biological Chemistry. Throughout evolution, Nature has developed molecular machines to rapidly manufacture, tailor, and deliver large functional biopolymers such as proteins into specific cells. Inspired by these mechanisms of nature, the Pentelute Lab has aimed to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins. he invention of new chemistry is sought to modify Nature’s proteins to enhance their therapeutic properties for human medicine. This goal has posed immense challenges because proteins contain 20 amino acids that present different reactive functional groups and have a 3D shape that is moderately stable. In light of these obstacles, the newly developed chemistry needs to be protein compatible, site-selective, quantitative, and carried out in water at reasonable temperatures to maintain protein integrity and function. The Pentelute Lab has met these challenges and has developed a series of highly efficient and selective chemistries that can modify the amino acid cysteine and lysine within peptides and proteins. These newly developed chemistries can be catalyzed by enzymes or even promoted by a motif discovered by Pentelute’s group, which is coined a ‘pi-clamp’. This extensive protein modification toolkit has enabled the production of some powerful molecules including peptide macrocycles that cross cell membranes to disrupt cancer or antibody drug conjugates to kill breast cancer cells.

The Pentelute group is also focused on the delivery of large biomolecules into the cell cytosol. The group has developed a chemical approach for the systematic investigation of a nontoxic form of anthrax toxin, which transports enzymes into cells via a protective antigen-protein pump. The Pentelute Lab has recently discovered that the protein pump can deliver a wide range of cargo molecules into cells including antibody mimics, mirror-image proteins, small molecules, and enzymes. Once in the cytosol, the cargo activates biologically and in certain cases perturbs protein-protein interactions that drive cancer. The Pentelute group made a noteworthy cell biology discovery with this biomolecular delivery platform: the act of simply installing a single D-amino acid on an otherwise large L-protein turns off a key mechanism for cytosolic protein degradation. This discovery will aid in the development of durable cell-based protein therapeutics.

The Pentelute group has also invented a fully automated fast-flow machine to accelerate the chemical manufacture of polypeptides. It has built the world’s fastest and most efficient machine that can produce thousands of amide-bonds orders of magnitude faster than commercially available instruments. The machine is inspired by Nature’s ribosome that can incorporate 9 amino acids into a polypeptide chain per second. While the Pentelute group’s fast-flow technology is not as fast as the ribosome, it can form one amide bond in 7 seconds. This technology not only facilitates rapid polypeptide generation but also has enabled the group to carry out an entire D-scan of proteins to investigate protein folding and functions. This technology may solve the manufacturing problem for personalized peptide cancer vaccines.

Pfizer Award in Enzyme Chemistry

Professor Mohammad Seyedsayamdost, Princeton University

For outstanding work in enzyme chemistry where the presence of enzyme action is unequivocally demonstrated.

Professor Mohammad R. Seyedsayamdost is the recipient of the 2018 Pfizer Award in Enzyme Chemistry in recognition of his contributions to the discovery of new enzymatic transformations in microbial systems. His research blends approaches from microbiology, bacterial genetics, natural products chemistry, and mechanistic enzymology to characterize the structures, functions, and biosynthesis of bacterial secondary metabolites. These metabolites are of importance to microbial communities, such as the human microbiome, and play decisive roles in human health and disease. One area of focus in the Seyedsayamdost group has been the identification of new metalloenzymes that catalyze unusual transformations during secondary metabolite biosynthesis. Specifically, his group characterized streptide, the founding member of a novel class of peptide natural products produced by the probiotic bacterium Streptococcus thermophilus. Structural elucidation of streptide revealed an unprecedented post-translational modification consisting of an intramolecular carbon-carbon crosslink between the side-chains of lysine and tryptophan. Further investigations showed that a new subfamily of radical SAM metalloenzymes install this unique modification in a single step, the mechanistic basis of which has been delineated in detail. Moreover, his group has examined the biosynthesis of the antibiotic drug-of-last resort, vancomycin, and demonstrated the involvement of cytochrome P450 metalloenzymes in creating some of the aromatic macrocycles, which endow the antibiotic with exquisite biological activity. Together, these studies have expanded our knowledge regarding the capabilities of metalloenzymes in synthesizing complex molecules; they have important implications for the utility of enzymes in the creation of designer natural products with desired biological functions.

The Repligen Award in Chemistry of Biological Processes

Professor Michael Gelb, University of Washington

For outstanding contributions to the understanding of biological processes with particular emphasis on structure, function and mechanism.

 

Prof. Michael Gelb is the winner of the 2018 Repligen Corporation Award in the Chemistry of Biological Processes in recognition of his research contributions in the area of enzymology applied to medicine. Major accomplishments have been made in 4 areas. The first is two decades or work with the late Mahendra Jain (Univ. of Delaware) and Otto Berg (Univ. of Uppsala) on developing the fundamental paradigm for studying the action of enzymes at the membrane-water interface (interfacial enzymology). This work has led to methods for the proper evaluation of enzyme inhibitors and substrate specificity of interfacial enzymes, most notably phospholipases. More recent work in this area have helped to understand the role of phospholipases A2 in pro-inflammatory eicosanoid cascades relevant to asthma and arthritis.

In the late 1980s, the Gelb lab in collaboration with the late John Glomset (Univ. of Washington) discovered a post-translational protein modification in eukaryotic cells called protein prenylation. The discovery that Ras proteins are farnesylated led to a massive campaign in pharma to develop novel anticancer drugs. Gelb and Glomset also discovered that most G-proteins are bound to membranes via 15-carbon farnesyl or 20-carbon geranylgeranyl groups.

The third area of research in the Gelb lab is aimed at discovery of new drugs for treating neglected diseases caused by parasites (malaria, African sleeping sickness, Chagas, and Leishmaniasis). Some of the top ranking pre-clinical drug candidates in this area have been put forward by the Gelb lab in collaboration with parasitologists Fred Buckner and Wes Van Voorhis (Univ. of Washington).

The final area, and the one that is prominent in Gelb’s lab now, is the use of mass spectrometry for quantitative proteomics and clinical chemistry. The Gelb lab developed Isotope-Coded Affinity Tag reagents (ICAT) in collaboration with Frank Turecek and Ruedi Aebersold (Univ. of Washington). As a team, Gelb, Turecek and C. Ronald Scott (Univ. of Washington) have advanced the use of tandem mass spectrometry for screening of newborns to detect inborn errors of metabolism, most notably lysosomal storage diseases. This work has led to the first worldwide effort to screen for these disorders and is rapidly becoming part of the newborn screening panels in each state’s newborn screening laboratory in the USA. With newborn screening in place, treatments for these diseases can be initiated before the onset of irreversible symptoms and lead on to a greatly improved quality of life for infants and children.


Gordon Hammes ACS Biochemistry Lectureship

Professor Vern L. Schramm

For outstanding contributions in scientific research at the interface of chemistry and biology, particularly in the realm of biochemistry, biological chemistry and molecular biology.

Professor Vern L. Schramm is the recipient of the 2018 Gordon Hammes ACS Biochemistry Lectureship. The Gordon Hammes Lecture Award is sponsored jointly by Biochemistry and the ACS Division of Biological Chemistry. The objective is to recognize and honor a single individual whose scientific contributions have had a significant impact on research at the interface of chemistry and biology. This year’s award goes to Professor Vern Schramm of the Albert Einstein College of Medicine.

“I am so incredibly thrilled that Vern has been selected as the winner of the Biochemistry 2018 Gordon Hammes Lectureship! The selection committee was unanimous and unanimously enthusiastic about his profound contributions to the field of biological chemistry”, says Alanna Schepartz, Editor-in-Chief of Biochemistry.

Schramm studied chemistry and microbiology for his B.S. at South Dakota State University. A scholarship for a master’s degree at the Harvard School of Public Health exposed him to nutrition and biochemistry. For his Ph.D. degree, he studied enzymatic mechanisms at the Australian National University with John Morrison during the time Morrison was deriving equations for tight-binding enzyme inhibitors.

Following an NRC-NSF postdoctoral fellowship at NASA Ames Research Center in California, Schramm began research in enzymatic reaction mechanisms and transition state analysis at the Department of Biochemistry, Temple University School of Medicine. In 1987 he was recruited to chair the Department of Biochemistry at the Albert Einstein College of Medicine, a position he held until 2015. He leads a research program in enzymology as Professor and Ruth Merns Chair of Biochemistry, the Schramm laboratory, which pioneered an approach to use intrinsic kinetic isotope effects combined with computational chemistry to understand the details of enzymatic transition states. Together with a team of chemistry collaborators in New Zealand, the Schramm laboratory designed and characterized the transition state analogs for a family of N-ribosyltransferases. These have proven to be powerful inhibitors. Three of the inhibitors designed by this approach have entered clinical trials, and others are in earlier development. Japan recently approved one analog for use in relapsed or resistant peripheral T cell lymphoma in Japan.

Schramm will present a talk and receive his award during the Gordon Hammes ACS Biochemistry Symposium during the Gordon Hammes ACS Biochemistry Symposium at the 256th ACS National Meeting & Exposition, held in Boston, Aug. 19-23, 2018.

Gordon Hammes ACS Biochemistry Scholar Award

Timothy Bumpus

To honor the young scientists resposible for the very best papers published in Biochemistry.

Timothy Bumpus is the recipient of the 2018 Gordon Hammes Scholar Award. The Gordon Hammes Scholar Award honors the young scientists responsible for the very best papers published in Biochemistry. Established in 2017 and awarded alongside the Gordon Hammes Lectureship Award, the Scholar Award seeks to recognize those at the bench – graduate students, postdocs, and undergraduates – for the outstanding work they do. The award is sponsored jointly by Biochemistry and the ACS Division of Biological Chemistry. Timothy Bumpus was selected as this year’s winner from a large applicant pool based on his first-author paper, “Ex Uno Plura: Differential Labeling of Phospholipid Biosynthetic Pathways with a Single Bioorthogonal Alcohol,” published earlier this year as part of the Future of Biochemistry Special Issue.

Bumpus is currently a National Science Foundation graduate research fellow in the Department of Chemistry & Chemical Biology at Cornell University studying under Professor Jeremy Baskin. After growing up on the East Coast, he moved to Iowa for his undergraduate studies and in 2015 received his bachelor’s degree from Luther College, with majors in chemistry, biology, and mathematics. There his thesis work focused on the design and synthesis of ecologically friendly bio-renewable and biodegradable plastics.

Bumpus says his current work focuses on “developing and implementing new chemical tools to study the role of lipid signaling in cell biology, particularly small-molecule probes which serve as substrate mimics and report on the enzymatic activity of phospholipase D. This will help elucidate the role of phosphatidic acid, the lipid product of phospholipase D, in cell signaling, and unravel the web of biosynthetic pathways which intersect at this pleiotropic lipid.”

Bumpus will present a talk describing his research and receive his award during the Gordon Hammes ACS Biochemistry Symposium at the 256th ACS National Meeting & Exposition, held in Boston, Aug. 19-23, 2018.

The ACS Chemical Biology Lectureship

Professor James A. Wells, University of California, San Francisco

For contributions that have had a major impact on scientific research in the area of Chemical Biology.

James A. Wells is the Harry Wm. and Diana V. Hind Distinguished Professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco. Dr. Wells’ selection as the recipient of the 2018 ACS Chemistry Biology Lectureship recognizes his groundbreaking research in detecting and attacking cancer surface proteomes with recombinant antibodies. This research involves the development of enabling technologies for protein engineering and drug discovery to understand biology and pave roads to therapeutics. His lab uses both mass spectrometry based technologies and a new multiplexed antibody method to systematically understand how cancer cells remodel their surface-omes, then toxify the antibodies, or recruit immune cells to kill these cancer cells. The cell surface proteome is an essential platform for cell–cell communication. The cellular changes caused by oncogenesis may also impact this cell surface-ome, making it a potential therapeutic target in the treatment of various cancers. The Wells group has used a powerful combination of proteomic and transcriptomic techniques to profile changes to the cell surface proteome induced by the expression of oncogenic KRas. They also employ genetically barcoded antibodies for highly multiplexed surface-ome profiling. Together, these techniques allowed mapping of the KRas cell surface, enabling the identification of cell surface proteins that are unique to cancer cells and thus possible therapeutic targets. Wells and co-workers have also generated chemical-epitope-selective antibodies that can act as antibody-based chemically induced dimerizers for the regulation of human cancer cell therapies. Dr. Wells presented this work on March 20, 2018 at the 255th ACS National Meeting and Exposition held in New Orleans.

The Biopolymers Murray Goodman Memorial Prize

Professor William F. DeGrado, University of California, San Francisco

For outstanding accomplishments in one or more of the areas of biochemistry, biophysical chemistry, biophysics, and/or chemical biology.

Professor William F. DeGrado is the recipient of the 2017 Biopolymers Murray Goodman Memorial Prize. The award is in recognition of Dr. DeGrado’s seminal contributions to the de novo design of peptides, proteins, and pharmaceutically active small molecules. He currently works as a Professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco. He received his Ph.D. from the University of Chicago. Thereafter he worked at the then named DuPont Merck Pharmaceutical Company and the University of Pennsylvania, before taking up his present position in 2011. He has co-authored over 370 articles, holds more than 25 patents, and has received several prestigious awards. These include the Protein Society’s Stein and Moore Award, the Rao Makineni Lectureship presented by the American Peptide Society, and the ACS Ralph F. Hirschmann Award in Peptide Chemistry. Dr. Degrado’s research group focuses on small molecule and protein design as an approach to understanding macromolecule structure and function. More specifically, the group carries out structural characterization of membrane proteins and de novo protein design in order to gain insight into biological processes relevant to human disease and to develop novel therapeutics. A recent example of their research reports the first ligand–binding protein designed from scratch, with the experimentally determined high-resolution structure matching the design with sub-angstrom accuracy. Dr. Degrado’s work has far-reaching implications for understanding human diseases, including HIV and Alzheimer’s disease.