Viewpoint Cite This: Biochemistry XXXX, XXX, XXX−XXX
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Functionalized Peptides: Ideal Targets for Collaborative Chemistry Justine N. deGruyter* Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
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iterative introduction of non-natural residues have found the greatest success and remain the standard modes of diversification in medicinal chemistry. Though in line with traditional methods of peptide construction (most notably, solid-phase peptide synthesis), this venerable approach severely limits opportunities for late-stage functionalization. As such, the direct and highly specific modification of fully elaborated sequences remains an enticing challenge.2 From an intellectual perspective, the inherent restrictions associated with peptides make for provocative targets in the development of methods; the ability to achieve a desired chemoselective transformation while operating under the strictest of reaction conditions (i.e., ambient temperature, neutral pH, aqueous media) speaks to incredible reaction fidelity and makes for an impressive addition to any substrate table. It is, however, difficult to imagine such works being conceived of, be it the identification of an existing problem or the machination of a solution, without the cooperation of two distinct bases of knowledge, a fact evidenced by recent contributions from several interdisciplinary teams. In a recent example, Buchwald and Pentelute3a (Figure 1A) disclosed a palladium-mediated cysteine arylation reaction, one of very few transition-metal-based transformations successfully applied to complex biomolecules.
he vast therapeutic potential of peptides and peptidomimetics has seen the accelerated advancement of complex biomolecules as drug candidates. Bucking the trends outlined by Lipinksi’s set of predictive rules, these compounds demonstrate a notable efficacy paired with the ability to engage targets deemed inaccessible by conventional small molecule drugs.1 Despite promising pharmacological profiles, improvement of metabolic stability and pharmacokinetics through structural alteration is often required, a challenge that, in many cases, remains unsatisfied. Much in the way that Nature requires the concerted effort of disparate machineries to achieve post-translational modifications, so, too, should this task compel a merging of scientific expertise if peptides are to escape the realm of “niche” medicinal interest.1 To this end, native sequences represent attractive therapeutic targets, as the ease of synthesis (extraordinarily robust and often automated) and ready availability of materials (abundant and inexpensive) lower many of the practical barriers encountered in bringing small molecules past initial stages of development. However, the control required for the precise modification of leads necessitated by any fruitful drug discovery campaign is challenged by the presence of dense and varied functional groups. Among the approaches for enhancement, macrocyclization and
Figure 1. Recent peptide functionalization methods developed by collaborative teams. Received: March 9, 2018
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DOI: 10.1021/acs.biochem.8b00298 Biochemistry XXXX, XXX, XXX−XXX
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approach for the chemoselective arylation of selenocysteine in unprotected peptides. J. Am. Chem. Soc. 137, 9784−9787. (c) Lee, H. G., Lautrette, G., Pentelute, B. L., and Buchwald, S. L. (2017) Palladium-mediated arylation of lysine in unprotected peptides. Angew. Chem., Int. Ed. 56, 3177−3181. (d) Rojas, A. J., Zhang, C., Vinogradova, E. V., Buchwald, N. H., Reilly, J., Pentelute, B. L., and Buchwald, S. L. (2017) Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation. Chem. Sci. 8, 4257−4263. (e) Rojas, A. J., Pentelute, B. L., and Buchwald, S. L. (2017) Water-soluble palladium reagents for cysteine S-arylation under ambient aqueous conditions. Org. Lett. 19, 4263−4266. (f) Kubota, K., Dai, P., Pentelute, B. L., and Buchwald, S. L. (2018) Palladium oxidative addition complexes for peptide and protein cross-linking. J. Am. Chem. Soc. 140, 3128−3133. (4) Malins, L. R., deGruyter, J. N., Robbins, K. J., Scola, P. M., Eastgate, M. D., Ghadiri, M. R., and Baran, P. S. (2017) Peptide macrocyclization inspired by non-ribosomal imine natural products. J. Am. Chem. Soc. 139, 5233−5241. (5) Lin, S., Yang, X., Jia, S., Weeks, A. M., Hornsby, M., Lee, P. S., Nichiporuk, R. V., Iavarone, A. T., Wells, J. A., Toste, F. D., and Chang, C. J. (2017) Redox-based reagents for chemoselective methionine bioconjugation. Science 355, 597−602 and references cited therein.
Of interest to those in pharmaceutical development, the technology not only enables rapid (∼5 min) and near-quantitative incorporation of high-value reactive handles, but also allows for peptide stapling through the use of an analogous bifunctional reagent. In a testament to the success of this partnership, the authors have published several additional methods targeting peptidic frames.3b−f In 2017, Baran and Ghadiri,4 in conjunction with Bristol-Myers Squibb, reported the development of an imine-based macrocyclization approach inspired by the nonribosomal peptide synthetase/reductase enzymatic sequence (Figure 1B). Noting that traditional approaches rely on a kinetically driven manifold, the authors devised a general protocol for the protecting-group-free thermodynamic macrocyclization of druglike peptide scaffolds. Shortly thereafter, Toste and Chang5 (Figure 1C) described the redox-activated chemical tagging of methionine via an uncommon oxaziridine N-transfer strategy to form a stable sulfimide. Importantly, this work makes a compelling case for the investigation of underexplored residues through the repurposing of known chemistries (e.g., sulfur imidation), a notion that has stimulated peptide-specific reaction discovery for decades.5 The broad adoption of peptides as viable drug candidates will first require mastery over the facile and discrete modification of native sequences; further exploration of each residue as a distinct chemical entity will prove vital in this initiative, as will continued collaborative efforts between small molecule groups and those that work near exclusively in the fields of peptide and protein synthesis. While it is certainly not the only way forwardcountless individual research groups that lie at the interface of the two fields have made exciting contributions to the literaturethere can be no doubt that a merging of complementary perspectives will further invigorate this already flourishing terrain. Finally, extension of this same logic to other classes of biomolecules (e.g., glycosides, oligonucleotides, etc.) should inspire the pursuit of the molecules of life as fascinating targets for interdisciplinary total synthesis.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Justine N. deGruyter: 0000-0003-0465-8988 Funding
Financial support for this work was provided by the National Science Foundation GRFP. Notes
The author declares no competing financial interest.
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ACKNOWLEDGMENTS Professor Phil S. Baran (The Scripps Research Institute) is gratefully acknowledged for helpful discussions. REFERENCES
(1) Henninot, A., Collins, J. C., and Nuss, J. M. (2018) The current state of peptide drug discovery: Back to the future? J. Med. Chem. 61, 1382−1414. (2) deGruyter, J. N., Malins, L. R., and Baran, P. S. (2017) Residuespecific peptide modification: A chemist’s guide. Biochemistry 56, 3863−3873. (3) (a) Vinogradova, E. V., Zhang, C., Spokoyny, A. M., Pentelute, B. L., and Buchwald, S. L. (2015) Organometallic palladium reagents for cysteine bioconjugation. Nature 526, 687−691. (b) Cohen, D. T., Zhang, C., Pentelute, B. L., and Buchwald, S. L. (2015) An umpolung B
DOI: 10.1021/acs.biochem.8b00298 Biochemistry XXXX, XXX, XXX−XXX
