Synthesis of homopolymers and copolymers containing an active ester of acrylic acid by RAFT: Scaffolds for controlling polyvalent ligand display

Abstract

We describe the synthesis of activated homopolymers and copolymers of controlled molecular weight based on the controlled radical polymerization of N-acryloyloxysuccinimide (NAS) by reversible addition fragmentation chain transfer (RAFT). We synthesized activated homopolymers in a range of molecular weights with polydispersities between 1 and 1.2. The attachment of an inhibitory peptide to the activated polymer backbone yielded a potent controlled molecular weight polyvalent inhibitor of anthrax toxin. To provide greater control over the placement of the peptides along the polymer backbone, we also used a semi-batch copolymerization method to synthesize copolymers of NAS and acrylamide (AAm). This approach enabled the synthesis of copolymers with control over the placement of peptide-reactive NAS monomers along an inert backbone; subsequent functionalization of NAS with peptide yielded well-defined polyvalent anthrax toxin inhibitors that differed in their potencies. These strategies for controlling molecular weight, ligand density, and ligand placement will be broadly applicable for designing potent polyvalent inhibitors for a variety of pathogens and toxins, and for elucidating structure-activity relationships in these systems.

Living Radical Polymerization by the RAFT Process - A Second Update

“…Styrene derivatives subjected to RAFT polymerization 348 [100,199] O 349 [138] O N N N 350 [158,309] N VBTAC 351 [159] Cl Ϫ Nϩ 352 [459] HN O 353 [321] O F F F F 354 [313] O F F F F 355 [313] [244] VBTPC 359 [34] Cl Ϫ P ϩ 360 [244] 361 [250] O N O 362 [207] O O O 363 [134] O O O Fe 364 [102] N 365 [102] N Table 23. Vinyl derivatives subjected to RAFT polymerization 366 [380] N 367 [380] N 368 [380] N 369 [390] N O O G. Moad, E. Rizzardo, and S. H. Thang [111,135] 370 [135,146] 375 [136] 376 [195] 377 [150] 378 [410] O O (H 3 C) 3 Si 372 [338,346,347] 373 [201] 374 [459] O [466] NAS 380 [160,299,317,345,347] 381 [178] 382 [222] [149,…”

“…RAFT polymerization has been used to synthesize the scaffolds for attachment of biopolymers by copolymerization of monomers shown in Table 24 (azide or alkyne functionality), Table 25 (active ester functionality, e.g., Scheme 29) for attachment of therapeutic agents, [317] peptides, [160,317] or DNA, [347] or Table 26 (e.g., pyridyl disulfide functionality (391), Scheme 30) for attachment of thiol residues of proteins (e.g., BSA), [162] or drug molecules. [161] The production of such scaffolds by RAFT and other RDRP processes for post polymerization modification has recently been reviewed.…”

“…BMA [139] MAA [140] MMA [64,141] AEMA [90,142] DEGMA [141] DMAEMA [143] DPAEMA [144] MAA [145] PEGMA [144,[146][147][148] 383 [149] DMAM [150] NIPAM [151] 274 [152,153] 325 [154] 326 [154] APMAM-b-NIPAM [89,152] AEMAM [153] St [155] 274 [153] 275 [153] 285 [156] 286 [156] 289 [157] 292 [158] 304 [140] 305 [140] 331 [159] 329 [140] 327 [157] 380 [160] 391 [161,162] 389 [104] (390) [104] 416 [163,164] MAA-b-280 [145] BMA-b-MPC [139] PEGMA/ 320 [165] PEGMA/344 [165] DEGMA-b-384 [141] MMA-b-384 …”

Design of Polyvalent Polymer Therapeutics

“…Here, we primarily highlight our studies on polymer-based scaffolds. Specifically, we discuss designing self-assembling polymeric micelles for use as polyvalent therapeutics [49,50], controlling the molecular weight and pendant ligand spacing for linear polymeric scaffolds [27,51,52] and matching the architecture of the scaffold to that of the target [53]. We also include some discussion on the use of polypeptide-based scaffolds [28], both in the context of synthetic polymers and with scaffolds designed by protein engineering methods.…”

“…While statistical interpretations of the characterization data could lead to deductions about valency and interligand spacing on average, it was hypothesized that more precise control over the placement of the activated monomers would help to gain an even more comprehensive understanding of the relationship between structure and activity in polyvalent systems. With this goal in mind, the semibatch RAFT polymerization approach described previously was modified to construct polymers with defined spacing between reactive monomers [52]. The first step was to determine the distances between ligands that are likely to provide a reasonable range of activity in the designed polyvalent inhibitor.…”