Chemical biology

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An overview of the different components included in the field of chemical biology Chemical biology flowchart.png
An overview of the different components included in the field of chemical biology

Chemical biology is a scientific discipline between the fields of chemistry and biology. The discipline involves the application of chemical techniques, analysis, and often small molecules produced through synthetic chemistry, to the study and manipulation of biological systems. [1] Although often confused with biochemistry, which studies the chemistry of biomolecules and regulation of biochemical pathways within and between cells, chemical biology remains distinct by focusing on the application of chemical tools to address biological questions. [2]

Contents

History

Although considered a relatively new scientific field, [2] the term "chemical biology" has been in use since the early 20th century, [3] and has roots in scientific discovery from the early 19th century. The term 'chemical biology' can be traced back to an early appearance in a book published by Alonzo E. Taylor in 1907 titled "On Fermentation", [4] and was subsequently used in John B. Leathes' 1930 article titled "The Harveian Oration on The Birth of Chemical Biology". [5] However, it is unclear when the term was first used. [3]

Friedrich Wöhler's 1828 synthesis of urea is an early example of the application of synthetic chemistry to advance biology. [6] It showed that biological compounds could be synthesized with inorganic starting materials and weakened the previous notion of vitalism, or that a 'living' source was required to produce organic compounds. [7] [8] Wöhler's work is often considered to be instrumental in the development of organic chemistry and natural product synthesis, both of which play a large part in modern chemical biology. [9]

Friedrich Miescher's work during the late 19th century investigating the cellular contents of human leukocytes led to the discovery of 'nuclein', which would later be renamed DNA. [6] After isolating the nuclein from the nucleus of leukocytes through protease digestion, Miescher used chemical techniques such as elemental analysis and solubility tests to determine the composition of nuclein. [10] This work would lay the foundations for Watson and Crick's discovery of the double-helix structure of DNA. [10] [11]

The rising interest into chemical biology has led to the creation of multiple journals dedicated to the field. Nature Chemical Biology, created in 2005, [12] and ACS Chemical Biology, created in 2006, [13] are two of the most well-known journals in this field, with impact factors of 14.8 [14] and 4.0 [15] respectively.   

Nobel laureates in chemical biology

List of Nobel laureates in chemical biology
LaureateYearDisciplineContribution
Paul Berg 1980Chemistry Recombinant DNA [16]
Walter Gilbert

Fredrick Sanger

1980Chemistry Genome sequencing [16]
Kary Mullis 1993Chemistry Polymerase chain reaction [17]
Michael Smith 1993Chemistry Site-directed mutagenesis [17]
Venkatraman Ramakrishnan

Thomas A. Steitz Ada E. Yonath

2009ChemistryElucidation of ribosome structure and function [18]
Robert J. Lefkowitz

Brian K. Kobilka

2012Chemistry G-protein-coupled receptors [19]
Frances H. Arnold

George P. Smith Gregory P. Winter

2018Chemistry Enzyme development through directed evolution [20]
Emmanuelle Charpentier

Jennifer A. Doudna

2020Chemistry CRISPR/Cas9 genetic scissors [21]
Barry Sharpless

Morten Meldal

2022Chemistry Click chemistry [22]
Carolyn Bertozzi 2022ChemistryApplications of click chemistry in living organisms [22]

Research areas

Glycobiology

Example of a sialic acid, a commonly studied molecule in glycobiology. Sialic acid created with Chemdraw.png
Example of a sialic acid, a commonly studied molecule in glycobiology.

Glycobiology is the study of the structure and function of carbohydrates. [23] While DNA, RNA and proteins are encoded at the genetic level, carbohydrates are not encoded directly from the genome, and thus require different tools for their study. [24] By applying chemical principles to glycobiology, novel methods for analyzing and synthesizing carbohydrates can be developed. [25] For example, cells can be supplied with synthetic variants of natural sugars to probe their function. Carolyn Bertozzi's research group has developed methods for site-specifically reacting molecules at the surface of cells via synthetic sugars. [26]

Combinatorial chemistry

The process of selecting a receptor in combinatorial chemistry. Receptor Selection by Dynamic Combinatorial Library.png
The process of selecting a receptor in combinatorial chemistry.

Combinatorial chemistry involves simultaneously synthesizing a large number of related compounds for high-throughput analysis. [27] Chemical biologists are able to use principles from combinatorial chemistry in synthesizing active drug compounds and maximizing screening efficiency. [28] Similarly, these principles can be used in areas of agriculture and food research, specifically in the syntheses of unnatural products and in generating novel enzyme inhibitors. [29]

Peptide synthesis

Solid phase peptide synthesis. Solid Phase Peptide Synthesis.jpg
Solid phase peptide synthesis.

Chemical synthesis of proteins is a valuable tool in chemical biology as it allows for the introduction of non-natural amino acids as well as residue specific incorporation of "posttranslational modifications" such as phosphorylation, glycosylation, acetylation, and even ubiquitination. [30] These properties are valuable for chemical biologists as non-natural amino acids can be used to probe and alter the functionality of proteins, while post-translational modifications are widely known to regulate the structure and activity of proteins. [31] Although strictly biological techniques have been developed to achieve these ends, the chemical synthesis of peptides often has a lower technical and practical barrier to obtaining small amounts of the desired protein. [32]

To make protein-sized polypeptide chains with the small peptide fragments made by synthesis, chemical biologists can use the process of native chemical ligation. [33] Native chemical ligation involves the coupling of a C-terminal thioester and an N-terminal cysteine residue, ultimately resulting in formation of a "native" amide bond. [34] Other strategies that have been used for the ligation of peptide fragments using the acyl transfer chemistry first introduced with native chemical ligation include expressed protein ligation, [35] sulfurization/desulfurization techniques, [36] and use of removable thiol auxiliaries. [37]

Enrichment techniques for proteomics

Chemical biologists work to improve proteomics through the development of enrichment strategies, chemical affinity tags, and new probes. Samples for proteomics often contain many peptide sequences and the sequence of interest may be highly represented or of low abundance, which creates a barrier for their detection. Chemical biology methods can reduce sample complexity by selective enrichment using affinity chromatography. This involves targeting a peptide with a distinguishing feature like a biotin label or a post translational modification. [38] Methods have been developed that include the use of antibodies, lectins to capture glycoproteins, and immobilized metal ions to capture phosphorylated peptides and enzyme substrates to capture select enzymes.

Enzyme probes

To investigate enzymatic activity as opposed to total protein, activity-based reagents have been developed to label the enzymatically active form of proteins (see Activity-based proteomics). For example, serine hydrolase- and cysteine protease-inhibitors have been converted to suicide inhibitors. [39] This strategy enhances the ability to selectively analyze low abundance constituents through direct targeting. [40] Enzyme activity can also be monitored through converted substrate. [41] Identification of enzyme substrates is a problem of significant difficulty in proteomics and is vital to the understanding of signal transduction pathways in cells. A method that has been developed uses "analog-sensitive" kinases to label substrates using an unnatural ATP analog, facilitating visualization and identification through a unique handle. [42]

Employing biology

Many research programs are also focused on employing natural biomolecules to perform biological tasks or to support a new chemical method. In this regard, chemical biology researchers have shown that DNA can serve as a template for synthetic chemistry, self-assembling proteins can serve as a structural scaffold for new materials, and RNA can be evolved in vitro to produce new catalytic function. Additionally, heterobifunctional (two-sided) synthetic small molecules such as dimerizers or PROTACs bring two proteins together inside cells, which can synthetically induce important new biological functions such as targeted protein degradation. [43]

Directed evolution

A primary goal of protein engineering is the design of novel peptides or proteins with a desired structure and chemical activity. [44] Because our knowledge of the relationship between primary sequence, structure, and function of proteins is limited, rational design of new proteins with engineered activities is extremely challenging. [45] In directed evolution, repeated cycles of genetic diversification followed by a screening or selection process, can be used to mimic natural selection in the laboratory to design new proteins with a desired activity. [46]

Several methods exist for creating large libraries of sequence variants. Among the most widely used are subjecting DNA to UV radiation or chemical mutagens, error-prone PCR, degenerate codons, or recombination. [47] [48] Once a large library of variants is created, selection or screening techniques are used to find mutants with a desired attribute. Common selection/screening techniques include FACS, [49] mRNA display, [50] phage display, and in vitro compartmentalization. [51] Once useful variants are found, their DNA sequence is amplified and subjected to further rounds of diversification and selection.

The development of directed evolution methods was honored in 2018 with the awarding of the Nobel Prize in Chemistry to Frances Arnold for evolution of enzymes, and George Smith and Gregory Winter for phage display. [52]

Bioorthogonal reactions

Successful labeling of a molecule of interest requires specific functionalization of that molecule to react chemospecifically with an optical probe. For a labeling experiment to be considered robust, that functionalization must minimally perturb the system. Unfortunately, these requirements are often hard to meet. Many of the reactions normally available to organic chemists in the laboratory are unavailable in living systems. [53] Water- and redox- sensitive reactions would not proceed, reagents prone to nucleophilic attack would offer no chemospecificity, and any reactions with large kinetic barriers would not find enough energy in the relatively low-heat environment of a living cell. [54] Thus, chemists have recently developed a panel of bioorthogonal chemistry that proceed chemospecifically, despite the milieu of distracting reactive materials in vivo.

The coupling of a probe to a molecule of interest must occur within a reasonably short time frame; [55] therefore, the kinetics of the coupling reaction should be highly favorable. Click chemistry is well suited to fill this niche, since click reactions are rapid, spontaneous, selective, and high-yielding. Unfortunately, the most famous "click reaction," a [3+2] cycloaddition between an azide and an acyclic alkyne, is copper-catalyzed, posing a serious problem for use in vivo due to copper's toxicity. To bypass the necessity for a catalyst, Carolyn R. Bertozzi's lab introduced inherent strain into the alkyne species by using a cyclic alkyne. In particular, cyclooctyne reacts with azido-molecules with distinctive vigor.

Discovery of biomolecules through metagenomics

The advances in modern sequencing technologies in the late 1990s allowed scientists to investigate DNA of communities of organisms in their natural environments ("eDNA"), without culturing individual species in the lab. This metagenomic approach enabled scientists to study a wide selection of organisms that were previously not characterized due in part to an incompetent growth condition. Sources of eDNA include soils, ocean, subsurface, hot springs, hydrothermal vents, polar ice caps, hypersaline habitats, and extreme pH environments. [56] Of the many applications of metagenomics, researchers such as Jo Handelsman, Jon Clardy, and Robert M. Goodman, explored metagenomic approaches toward the discovery of biologically active molecules such as antibiotics. [57]

Overview of metagenomic methods Overview of metagenomic methods.jpg
Overview of metagenomic methods

Functional or homology screening strategies have been used to identify genes that produce small bioactive molecules. Functional metagenomic studies are designed to search for specific phenotypes that are associated with molecules with specific characteristics. Homology metagenomic studies, on the other hand, are designed to examine genes to identify conserved sequences that are previously associated with the expression of biologically active molecules. [58]

Functional metagenomic studies enable the discovery of novel genes that encode biologically active molecules. These assays include top agar overlay assays where antibiotics generate zones of growth inhibition against test microbes, and pH assays that can screen for pH change due to newly synthesized molecules using pH indicator on an agar plate. [59] Substrate-induced gene expression screening (SIGEX), a method to screen for the expression of genes that are induced by chemical compounds, has also been used to search for genes with specific functions. [59] Homology-based metagenomic studies have led to a fast discovery of genes that have homologous sequences as the previously known genes that are responsible for the biosynthesis of biologically active molecules. As soon as the genes are sequenced, scientists can compare thousands of bacterial genomes simultaneously. [58] The advantage over functional metagenomic assays is that homology metagenomic studies do not require a host organism system to express the metagenomes, thus this method can potentially save the time spent on analyzing nonfunctional genomes. These also led to the discovery of several novel proteins and small molecules. [60] In addition, an in silico examination from the Global Ocean Metagenomic Survey found 20 new lantibiotic cyclases. [61]

Kinases

Posttranslational modification of proteins with phosphate groups by kinases is a key regulatory step throughout all biological systems. Phosphorylation events, either phosphorylation by protein kinases or dephosphorylation by phosphatases, result in protein activation or deactivation. These events have an impact on the regulation of physiological pathways, which makes the ability to dissect and study these pathways integral to understanding the details of cellular processes. There exist a number of challenges—namely the sheer size of the phosphoproteome, the fleeting nature of phosphorylation events and related physical limitations of classical biological and biochemical techniques—that have limited the advancement of knowledge in this area. [62]

Through the use of small molecule modulators of protein kinases, chemical biologists have gained a better understanding of the effects of protein phosphorylation. For example, nonselective and selective kinase inhibitors, such as a class of pyridinylimidazole compounds [63] are potent inhibitors useful in the dissection of MAP kinase signaling pathways. These pyridinylimidazole compounds function by targeting the ATP binding pocket. Although this approach, as well as related approaches, [64] [65] with slight modifications, has proven effective in a number of cases, these compounds lack adequate specificity for more general applications. Another class of compounds, mechanism-based inhibitors, combines knowledge of the kinase enzymology with previously utilized inhibition motifs. For example, a "bisubstrate analog" inhibits kinase action by binding both the conserved ATP binding pocket and a protein/peptide recognition site on the specific kinase. [66] Research groups also utilized ATP analogs as chemical probes to study kinases and identify their substrates. [67] [68] [69]

The development of novel chemical means of incorporating phosphomimetic amino acids into proteins has provided important insight into the effects of phosphorylation events. Phosphorylation events have typically been studied by mutating an identified phosphorylation site (serine, threonine or tyrosine) to an amino acid, such as alanine, that cannot be phosphorylated. However, these techniques come with limitations and chemical biologists have developed improved ways of investigating protein phosphorylation. By installing phospho-serine, phospho-threonine or analogous phosphonate mimics into native proteins, researchers are able to perform in vivo studies to investigate the effects of phosphorylation by extending the amount of time a phosphorylation event occurs while minimizing the often-unfavorable effects of mutations. Expressed protein ligation, has proven to be successful techniques for synthetically producing proteins that contain phosphomimetic molecules at either terminus. [70] In addition, researchers have used unnatural amino acid mutagenesis at targeted sites within a peptide sequence. [71] [72]

Advances in chemical biology have also improved upon classical techniques of imaging kinase action. For example, the development of peptide biosensors—peptides containing incorporated fluorophores improved temporal resolution of in vitro binding assays. [73] One of the most useful techniques to study kinase action is Fluorescence Resonance Energy Transfer (FRET). To utilize FRET for phosphorylation studies, fluorescent proteins are coupled to both a phosphoamino acid binding domain and a peptide that can by phosphorylated. Upon phosphorylation or dephosphorylation of a substrate peptide, a conformational change occurs that results in a change in fluorescence. [74] FRET has also been used in tandem with Fluorescence Lifetime Imaging Microscopy (FLIM) [75] or fluorescently conjugated antibodies and flow cytometry [76] to provide quantitative results with excellent temporal and spatial resolution.

Biological fluorescence

Chemical biologists often study the functions of biological macromolecules using fluorescence techniques. The advantage of fluorescence versus other techniques resides in its high sensitivity, non-invasiveness, safe detection, and ability to modulate the fluorescence signal. In recent years, the discovery of green fluorescent protein (GFP) by Roger Y. Tsien and others, hybrid systems and quantum dots have enabled assessing protein location and function more precisely. [77] Three main types of fluorophores are used: small organic dyes, green fluorescent proteins, and quantum dots. Small organic dyes usually are less than 1 kDa, and have been modified to increase photostability and brightness, and reduce self-quenching. Quantum dots have very sharp wavelengths, high molar absorptivity and quantum yield. Both organic dyes and quantum dyes do not have the ability to recognize the protein of interest without the aid of antibodies, hence they must use immunolabeling. Fluorescent proteins are genetically encoded and can be fused to your protein of interest. Another genetic tagging technique is the tetracysteine biarsenical system, which requires modification of the targeted sequence that includes four cysteines, which binds membrane-permeable biarsenical molecules, the green and the red dyes "FlAsH" and "ReAsH", with picomolar affinity. Both fluorescent proteins and biarsenical tetracysteine can be expressed in live cells, but present major limitations in ectopic expression and might cause a loss of function.

Fluorescent techniques have been used assess a number of protein dynamics including protein tracking, conformational changes, protein–protein interactions, protein synthesis and turnover, and enzyme activity, among others. Three general approaches for measuring protein net redistribution and diffusion are single-particle tracking, correlation spectroscopy and photomarking methods. In single-particle tracking, the individual molecule must be both bright and sparse enough to be tracked from one video to the other. Correlation spectroscopy analyzes the intensity fluctuations resulting from migration of fluorescent objects into and out of a small volume at the focus of a laser. In photomarking, a fluorescent protein can be dequenched in a subcellular area with the use of intense local illumination and the fate of the marked molecule can be imaged directly. Michalet and coworkers used quantum dots for single-particle tracking using biotin-quantum dots in HeLa cells. [78] One of the best ways to detect conformational changes in proteins is to label the protein of interest with two fluorophores within close proximity. FRET will respond to internal conformational changes result from reorientation of one fluorophore with respect to the other. One can also use fluorescence to visualize enzyme activity, typically by using a quenched activity-based proteomics (qABP). Covalent binding of a qABP to the active site of the targeted enzyme will provide direct evidence concerning if the enzyme is responsible for the signal upon release of the quencher and regain of fluorescence. [79]

Education in chemical biology

Undergraduate education

Despite an increase in biological research within chemistry departments, attempts at integrating chemical biology into undergraduate curricula are lacking. [80] For example, although the American Chemical Society (ACS) requires for foundational courses in a Chemistry Bachelor's degree to include biochemistry, no other biology-related chemistry course is required. [81]

Although a chemical biology course is often not required for an undergraduate degree in Chemistry, many universities now provide introductory chemical biology courses for their undergraduate students. The University of British Columbia, for example, offers a fourth-year course in synthetic chemical biology. [82]

See also

Related Research Articles

<span class="mw-page-title-main">Protein</span> Biomolecule consisting of chains of amino acid residues

Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific 3D structure that determines its activity.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">Proteomics</span> Large-scale study of proteins

Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In addition, other kinds of proteins include antibodies that protect an organism from infection, and hormones that send important signals throughout the body.

<span class="mw-page-title-main">Fluorescent tag</span>

In molecular biology and biotechnology, a fluorescent tag, also known as a fluorescent label or fluorescent probe, is a molecule that is attached chemically to aid in the detection of a biomolecule such as a protein, antibody, or amino acid. Generally, fluorescent tagging, or labeling, uses a reactive derivative of a fluorescent molecule known as a fluorophore. The fluorophore selectively binds to a specific region or functional group on the target molecule and can be attached chemically or biologically. Various labeling techniques such as enzymatic labeling, protein labeling, and genetic labeling are widely utilized. Ethidium bromide, fluorescein and green fluorescent protein are common tags. The most commonly labelled molecules are antibodies, proteins, amino acids and peptides which are then used as specific probes for detection of a particular target.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

In biochemistry, dephosphorylation is the removal of a phosphate (PO43−) group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deactivate enzymes by detaching or attaching phosphoric esters and anhydrides. A notable occurrence of dephosphorylation is the conversion of ATP to ADP and inorganic phosphate.

<span class="mw-page-title-main">Stable isotope labeling by amino acids in cell culture</span>

Stable Isotope Labeling by/with Amino acids in Cell culture (SILAC) is a technique based on mass spectrometry that detects differences in protein abundance among samples using non-radioactive isotopic labeling. It is a popular method for quantitative proteomics.

Chemical modification refers to a number of various processes involving the alteration of the chemical constitution or structure of molecules.

<span class="mw-page-title-main">Fusion protein</span> Protein created by joining other proteins into a single polypeptide

Fusion proteins or chimeric (kī-ˈmir-ik) proteins are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this fusion gene results in a single or multiple polypeptides with functional properties derived from each of the original proteins. Recombinant fusion proteins are created artificially by recombinant DNA technology for use in biological research or therapeutics. Chimeric or chimera usually designate hybrid proteins made of polypeptides having different functions or physico-chemical patterns. Chimeric mutant proteins occur naturally when a complex mutation, such as a chromosomal translocation, tandem duplication, or retrotransposition creates a novel coding sequence containing parts of the coding sequences from two different genes. Naturally occurring fusion proteins are commonly found in cancer cells, where they may function as oncoproteins. The bcr-abl fusion protein is a well-known example of an oncogenic fusion protein, and is considered to be the primary oncogenic driver of chronic myelogenous leukemia.

<span class="mw-page-title-main">Quantitative proteomics</span> Analytical chemistry technique

Quantitative proteomics is an analytical chemistry technique for determining the amount of proteins in a sample. The methods for protein identification are identical to those used in general proteomics, but include quantification as an additional dimension. Rather than just providing lists of proteins identified in a certain sample, quantitative proteomics yields information about the physiological differences between two biological samples. For example, this approach can be used to compare samples from healthy and diseased patients. Quantitative proteomics is mainly performed by two-dimensional gel electrophoresis (2-DE), preparative native PAGE, or mass spectrometry (MS). However, a recent developed method of quantitative dot blot (QDB) analysis is able to measure both the absolute and relative quantity of an individual proteins in the sample in high throughput format, thus open a new direction for proteomic research. In contrast to 2-DE, which requires MS for the downstream protein identification, MS technology can identify and quantify the changes.

<span class="mw-page-title-main">Protein phosphorylation</span> Process of introducing a phosphate group on to a protein

Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural conformation of a protein, causing it to become activated, deactivated, or otherwise modifying its function. Approximately 13,000 human proteins have sites that are phosphorylated.

Alice Yen-Ping Ting is Taiwanese-born American chemist. She is a professor of genetics, of biology, and by courtesy, of chemistry at Stanford University. She is also a Chan Zuckerberg Biohub investigator and a member of the National Academy of Sciences.

<span class="mw-page-title-main">Single-cell analysis</span> Testbg biochemical processes and reactions in an individual cell

In the field of cellular biology, single-cell analysis and subcellular analysis is the study of genomics, transcriptomics, proteomics, metabolomics and cell–cell interactions at the single cell level. The concept of single-cell analysis originated in the 1970s. Before the discovery of heterogeneity, single-cell analysis mainly referred to the analysis or manipulation of an individual cell in a bulk population of cells at a particular condition using optical or electronic microscope. To date, due to the heterogeneity seen in both eukaryotic and prokaryotic cell populations, analyzing a single cell makes it possible to discover mechanisms not seen when studying a bulk population of cells. Technologies such as fluorescence-activated cell sorting (FACS) allow the precise isolation of selected single cells from complex samples, while high throughput single cell partitioning technologies, enable the simultaneous molecular analysis of hundreds or thousands of single unsorted cells; this is particularly useful for the analysis of transcriptome variation in genotypically identical cells, allowing the definition of otherwise undetectable cell subtypes. The development of new technologies is increasing our ability to analyze the genome and transcriptome of single cells, as well as to quantify their proteome and metabolome. Mass spectrometry techniques have become important analytical tools for proteomic and metabolomic analysis of single cells. Recent advances have enabled quantifying thousands of protein across hundreds of single cells, and thus make possible new types of analysis. In situ sequencing and fluorescence in situ hybridization (FISH) do not require that cells be isolated and are increasingly being used for analysis of tissues.

<i>O</i>-GlcNAc

O-GlcNAc is a reversible enzymatic post-translational modification that is found on serine and threonine residues of nucleocytoplasmic proteins. The modification is characterized by a β-glycosidic bond between the hydroxyl group of serine or threonine side chains and N-acetylglucosamine (GlcNAc). O-GlcNAc differs from other forms of protein glycosylation: (i) O-GlcNAc is not elongated or modified to form more complex glycan structures, (ii) O-GlcNAc is almost exclusively found on nuclear and cytoplasmic proteins rather than membrane proteins and secretory proteins, and (iii) O-GlcNAc is a highly dynamic modification that turns over more rapidly than the proteins which it modifies. O-GlcNAc is conserved across metazoans.

PRIME is a molecular biology research tool developed by Alice Y. Ting and the Ting Lab at MIT for site-specific labeling of proteins in living cells with chemical probes. Probes often have useful biophysical properties, such as fluorescence, and allow imaging of proteins. Ultimately, PRIME enables scientists to study functions of specific proteins of interest.

Chemoproteomics entails a broad array of techniques used to identify and interrogate protein-small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of alleviating a disease phenotype, as opposed to target-based drug discovery, in which lead compounds are designed to interact with predetermined disease-driving biological targets. As phenotypic drug discovery assays do not provide confirmation of a compound's mechanism of action, chemoproteomics provides valuable follow-up strategies to narrow down potential targets and eventually validate a molecule's mechanism of action. Chemoproteomics also attempts to address the inherent challenge of drug promiscuity in small molecule drug discovery by analyzing protein-small molecule interactions on a proteome-wide scale. A major goal of chemoproteomics is to characterize the interactome of drug candidates to gain insight into mechanisms of off-target toxicity and polypharmacology.

Bradley Lether Pentelute is currently a professor of chemistry at the Massachusetts Institute of Technology (MIT). His research program lies at the intersection of chemistry and biology and develops bioconjugation strategies, cytosolic delivery platforms, and rapid flow synthesis technologies to optimize the production, achieve site-specific modification, enhance stability, and modulate function of a variety of bioactive agents. His laboratory successfully modified proteins via cysteine-containing “pi-clamps” made up of a short sequence of amino acids, and delivered large biomolecules, such as various proteins and drugs, into cells via the anthrax delivery vehicle. Pentelute has also made several key contributions to automated synthesis technologies in flow. These advances includes the invention of the world's fastest polypeptide synthesizer. This system is able to form amide bonds at a more efficient rate than standard commercial equipment and has helped in the process of understanding protein folding and its mechanisms. This automated flow technology was recently used to achieve total chemical synthesis of protein chains up to 164 amino acids in length that retained the structure and function of native variants obtained by recombinant expression. The primary goal of his endeavor is to use these processes to create designer biologics that can be used to treat diseases and solve the manufacturing problem for on-demand personalized therapies, such as cancer vaccines.

Jin Zhang is a Chinese-American biochemist. She is a professor of pharmacology, chemistry and biochemistry, and biomedical engineering at the University of California, San Diego.

Barbara Imperiali is a Professor of Biology and Chemistry at Massachusetts Institute of Technology and Affiliate Member of the Broad Institute. She is an elected member of the National Academy of Sciences and a Fellow of the Royal Society of Chemistry.

James Allen Wells is a Professor of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at the University of California, San Francisco (UCSF) and a member of the National Academy of Sciences. He received his B.A. degrees in biochemistry and psychology from University of California, Berkeley in 1973 and a PhD in biochemistry from Washington State University with Ralph Yount, PhD in 1979. He completed his postdoctoral studies at Stanford University School of Medicine with George Stark in 1982. He is a pioneer in protein engineering, phage display, fragment-based lead discovery, cellular apoptosis, and the cell surface proteome.

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