Chemists have developed a new set of reagents that can attach useful molecules to a specific, rarely-used building block in proteins—the amino acid methionine—in under a minute, with over 95% efficiency, in plain water. Most current methods for chemically modifying proteins rely on just two amino acids, cysteine and lysine, which limits what scientists can build. Methionine is an attractive alternative: it is rare in proteins (less than 2% abundance), plays a limited structural role, and contains a sulphur atom that can be selectively targeted. Until recently, no practical method existed for this. The researchers have now created hypervalent iodine salts—called MetSIS reagents—that react selectively with methionine residues, forming stable conjugates without disrupting the protein’s shape or function. This is fundamental chemistry that expands the toolkit for protein engineering. If successful, it could allow researchers to attach drugs, imaging probes, or synthetic handles to proteins at sites that were previously inaccessible. That could improve the design of antibody-drug conjugates, enable more precise biological sensors, or simplify the production of modified enzymes for industrial processes. Because the method works in water at room temperature, it is compatible with living systems, raising the possibility of modifying proteins inside cells. The work is at an early, curiosity-driven stage, but past breakthroughs in selective protein chemistry—such as cysteine-based labelling—have directly enabled many modern biotherapeutics and diagnostic tools.
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Nature routinely carries out site-selective modification of proteins, enabling a dramatic increase in functional diversity. In contrast, synthetic manipulation of proteins is restricted by the availability of suitable chemical transformations. However, access to synthetically modified proteins has become fundamentally important to chemical biology, molecular biology & medicine. This has stimulated intensive research into the development of chemical transformations that are compatible with biological systems. Ideally, a reaction should be selective at a single site on a protein at a rate that is commensurate with the kinetic demands of complex molecules; should operate under ambient conditions to prevent disruption of the protein architecture or function; & provide homogeneous products in near perfect conversion. Despite these challenges, the past 20 years have seen a number of exciting methodologies emerge for executing transformations, both in vitro & in vivo, at natural & non-natural amino-acid residues in proteins. While most chemical methods have focussed on expanding the toolkit for reaction at cysteine (Cys) & lysine (Lys) residues, there has been burgeoning interest in transformations at non-natural amino acids (via genetic encoding) that display side chain functionality with orthogonal reactivity to standard residues. Reagents that probe biological processes tend to rely on relatively simple reactions to circumvent problems with chemistry in complex environments. However, there is a need for complementary tools (to reactions at Cys & Lys) that selectively produce functional protein conjugates via previously unexplored amino acids. Methionine (Met) is a proteogenic amino acids & displays a number of features which make it potentially amenable as a bioconjugation target: For example, Met has a <2% abundance in proteins, is easily encoded, has a limited role in ancillary protein function (mainly protection against oxidative stress) & contains a possible reactive handle via its weakly nucleophilic S-atom. Until recently, practical Met-selective bioconjugation was unknown. Concurrent with our initial work, Chang et al reported a redox-activated tagging strategy that converted Met to sulfoximine-derivatives & successfully applying it in biology-driven applications. We have developed a methionine-selective protein functionalization strategy based on the use of hypervalent iodine reagents (we call these reagents MetSIS, meaning Methionine Selective Iodonium Salts) that react selectively with polypeptides & proteins, often giving >95% conversion to a stable diazo-sulfonium conjugate at low concentration in H2O in <1 minute. Our initial work on Met-bioconjugation was recently published Nature 2018, 562, 563-568. The structural diversity of the proteome in any single organism means that no one protein functionalization method will provide universal solutions to the preparation of protein constructs. Cys-ligation is the benchmark for protein labelling and is is fast, selective and continues to evolve powerful methods that can be applied to a plethora of chemical biology & bio-medical applications. Even though Cys has founded many distinct applications, what if another amino acid can be generally harnessed for protein functionalization that is complementary to Cys? Here, I propose that chemical targeting of methionine (Met) can be the basis of distinct strategies for protein modification. Through this Fellowship, I outline a program for synthesis-driven protein functionalization, where these biomacromolecules are labelled at Met for use in vitro & (possibly) in vivo environments thereby expanding the tools available to chemical biologists. Parallel lines of enquiry (Phases A&B) will generate protein functionalization tools & synergistically feed into a Phase C, which will seek to translate the synthesis advances to application.
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