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]

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

Research areas

Glycobiology

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

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 "

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

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;

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

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

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

• Chemoproteomics
• Chemical genetics
• Chemogenomics

References