Peptides as Drugs: Discovery and Development

Groner, Bernd

doi:10.1002/9783527626830.ch1

Cited by 30 publications

(31 citation statements)

References 28 publications

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“…Should this be the case, the use of H 2 18 O would provide the 18 O-labeled amide. In the event, we observed the formation of only 16 O-labeled amide (Table 1, entry 1), suggestive of a pathway to amide that might be more complex. The experiments that followed attempted to isolate the possible sources of oxygen: 1) residual water, 2) the nitro functionality in the α-halo nitroalkane substrate, and 3) potassium carbonate.…”

Section: Resultsmentioning

confidence: 99%

“…This understanding was used to develop a straightforward protocol for the preparation of 18 O-labeled amides in peptides by simply performing the umpolung amide synthesis reaction under an atmosphere of 18 O 2 . P reparative needs in amide synthesis, particularly those in the peptide regime, continue to drive new methods for their construction (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The increasing success of peptide therapeutics, as well as continuing biophysical studies of peptides, have generally outpaced the scope of purely chemical methods for their preparation on scale (16,17). Native chemical ligation has teamed with solid phase peptide synthesis to target an increasing list of complex problems, whereas α-keto acid-based methods (18,19) and umpolung amide synthesis (UmAS) (20) are beginning to target others.…”

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confidence: 99%

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Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide ¹⁸ O-labeling

Shackleford

Shen

Johnston

2011

Proc. Natl. Acad. Sci. U.S.A.

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The mechanism of umpolung amide synthesis was probed by interrogating potential sources for the oxygen of the product amide carbonyl that emanates from the α-bromo nitroalkane substrate. Using a series of 18 O-labeled substrates and reagents, evidence is gathered to advance two pathways from the putative tetrahedral intermediate. Under anaerobic conditions, a nitro-nitrite isomerization delivers the amide oxygen from nitro oxygen. The same homolytic nitro-carbon fragmentation can be diverted by capture of the carbon radical intermediate with oxygen gas (O 2 ) to deliver the amide oxygen from O 2 . This understanding was used to develop a straightforward protocol for the preparation of 18 O-labeled amides in peptides by simply performing the umpolung amide synthesis reaction under an atmosphere of .

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide ¹⁸ O-labeling

Shackleford

Shen

Johnston

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Synthetic peptides that target "hot spots" on protein surfaces are a logical entry to drug-discovery programs (15)(16)(17)(18)(19). However, native peptides generally have poor pharmacological properties (20). Modifications that offset those limitations while stably recapitulating proteinbinding conformations are of considerable interest (14,(21)(22)(23).…”

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confidence: 99%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

Proc. Natl. Acad. Sci. U.S.A.

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Peptide-protein interactions are important mediators of cellularsignaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. S ynthetic peptides and peptidomimetics play wide-ranging roles in pharmacology and drug discovery. Interest in these substances continues to grow, particularly as medicinal chemistry pushes further into control of cellular-signaling events mediated by protein-protein interactions (PPIs) (1-3). The subset of socalled "druggable" PPIs includes those mediated by consensus peptides, where binding determinants are localized within defined motifs (4-8). Experimental data as well as computational/ bioinformatic efforts (9-11) to identify "short linear motifs" within signaling proteins suggest that the number of druggable PPIs has been underestimated (12, 13). Considerable opportunity exists for new chemistry in this area (14). Synthetic peptides that target "hot spots" on protein surfaces are a logical entry to drug-discovery programs (15-19). However, native peptides generally have poor pharmacological properties (20). Modifications that offset those limitations while stably recapitulating proteinbinding conformations are of considerable interest (14,(21)(22)(23).Ring-forming reactions are prominent among alterations found to improve the stability and performance of peptides (24-27). They find broad utility in synthesis and, increasingly, in combination with phage, ribosome, and mRNA display technologies (28-32). Relative to their acyclic counterparts, cyclic peptides have more defined conformations and are less prone to aggregate (33). Head-to-tail lactamization is the most common method to synthesize cyclic peptides (34-36). Internal disulfide bonding is also used (37, 38), as are newer techniques such as ring-closing olefin metathesis (39) and catalyzed cycloaddition of azides to alkynes (40-42). These procedures rely on judicious use of protecting groups and/or tailored amino acid residues (Fig. 1A) (43, 44). Careful attention must be paid to...

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“…The crucial importance of peptides in biological systems and their potent therapeutic activity [1][2][3][4] has increased the demand for efficient preparative methods. Synthetic access to proteins allows changes to be made in their covalent structure and enables specific labelling of a protein.…”

Section: Introductionmentioning

confidence: 99%

Chemical ligation from O-acyl isopeptides via 8- and 11-membered cyclic transition states

Panda¹,

Elagawany²,

Marwani³

et al. 2014

Arkivoc

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Peptides as Drugs: Discovery and Development

Cited by 30 publications

References 28 publications

Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide ¹⁸ O-labeling

Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide ¹⁸ O-labeling

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Chemical ligation from O-acyl isopeptides via 8- and 11-membered cyclic transition states

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Peptides as Drugs: Discovery and Development

Cited by 30 publications

References 28 publications

Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide 18 O-labeling

Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide 18 O-labeling

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Chemical ligation from O-acyl isopeptides via 8- and 11-membered cyclic transition states

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Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide ¹⁸ O-labeling

Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide ¹⁸ O-labeling