Versatile Synthesis of Stable, Functional Polypeptides via Reaction with Epoxides

Abstract

Methodology was developed for efficient alkylation of methionine residues using epoxides as a general strategy to introduce a wide range of functional groups onto polypeptides. Use of a spacer between epoxide and functional groups further allowed addition of sterically demanding functionalities. Contrary to other methods to alkylate methionine residues, epoxide alkylations allow the reactions to be conducted in wet protic media and give sulfonium products that are stable against dealkylation. These functionalizations are notable since they are chemoselective, utilize stable and readily available epoxides, and allow facile incorporation of an unprecedented range of functional groups onto simple polypeptides using stable linkages.

Oxidation-Responsive and “Clickable” Poly(ethylene glycol) via Copolymerization of 2-(Methylthio)ethyl Glycidyl Ether

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Dealkylation or elimination during work-up of the reaction have not been observed. In summary, alkoxylated PEG-PMTEGE copolymers are stable at ambient temperatures similar to the reported alkoxylated poly(L-methionine) 3 and enlarge the toolbox for highly functional sulfonium polyelectrolytes with polar polyether backbone.…”

“…3 In an analogous manner, we can manipulate the reactivity of MTEGE by pH: At high pH, the nucleophilicity of the sulfide is not sufficient to ring-open an epoxide, and controlled AROP of the monomer can proceed, while at low pH the epoxide is activated and the sulfur(II) species is able to attack the epoxide ring. We studied this concept by addition of epichlorohydrin (ECH) ( Figure S35), allyl glycidyl ether (AGE) ( Figure S36) and glycidyl…”

“…1 At first glance, thioethers may seem rather unreactive and unspectacular, particularly compared to their thiol or disulfide analogues and thus have often been overlooked as a functional group by themselves. However, in contrast to regular ethers, the nature of sulfur provides the possibility to functionalize thioethers via oxidation, alkylation and alkoxylation [1][2][3][4] which can lead to interesting material properties. In the 1970ies,…”

Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins

“…3,4 Numerous strategies, including biological 8 and chemical synthesis, 1,2 have been developed to either react with or modify natural residues, or replace them entirely, using highly selective processes. Many of these methods have focused on reaction at or replacement of L-cysteine (Cys), 9 L-methionine (Met), 8,10,11 and N-terminal residues 12,13 since these are often present in low abundance and thus can provide unique sites for functional modification. Most chemical strategies have focused on reactions at highly nucleophilic Cys thiol groups, where a variety of different types of modification are possible.…”

Role of Side-Chain Molecular Features in Tuning Lower Critical Solution Temperatures (LCSTs) of Oligoethylene Glycol Modified Polypeptides

“…24,25 This methodology allowed us to rapidly and efficiently synthesize a systematic series of OEG functionalized polypeptides, which contained an unprecedented level of side-chain diversity ( Figure 1). In these samples, the number of EG repeats was varied from 1 to 3, and the EG terminal groups were also varied to include H, Ac, Me, and Et.…”