In biology, lipids are well known for their ability to assemble into spherical vesicles. Proteins, in particular virus capsids, can also form regular vesicle-like structures, where the precise folding and stable conformations of many identical subunits directs their self-assembly. Functionality present on these subunits also controls their disassembly within the cellular environment, for example, in response to a pH change. Here, we report the preparation of diblock copolypeptides that self-assemble into spherical vesicular assemblies whose size and structure are dictated primarily by the ordered conformations of the polymer segments, in a manner similar to viral capsid assembly. Furthermore, functionality was incorporated into these molecules to render them susceptible to environmental stimuli, which is desirable for drug-delivery applications. The control of assembly and function exhibited in these systems is a significant advance towards the synthesis of materials that can mimic the precise three-dimensional assembly found in proteins.

Water soluble copolypeptides containing l-dihydroxyphenylalanine (DOPA) and l-lysine were prepared by ring-opening polymerization of alpha-amino acid N-carboxyanhydride (NCA) monomers. We have prepared a range of different copolymers to probe the effects of functional group composition on adhesive and cross-linking behavior. Aqueous solutions of these copolymers, when mixed with a suitable oxidizing agent (e.g., O2, mushroom tyrosinase, Fe3+, H2O2, or IO4-), formed cross-linked networks that were found to form moisture-resistant adhesive bonds to a variety of substrates (e.g., aluminum, steel, glass, and plastics). It was found that successful adhesive formation was dependent on oxidation conditions, with chemical oxidants giving the best results. Optimized systems were found to form adhesive bonds that rival in strength those formed by natural marine adhesive proteins. Our synthetic systems are readily prepared in large quantities and require no enzymes or other biological components.

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A review of recent developments in polypeptide synthesis is provided. This article is focused on development of new materials based on polypeptides rather than on reproduction or applications of natural protein-based materials. Synthetic methods fall into two major categories: biological and chemical. The most successful biological approaches utilize cellular protein synthesis machinery to perform the task of assembling the polymeric molecules. Adaptation of this machinery for production of new, artificial polypeptide sequences and use of this machinery for incorporation of artificial amino acids into polypeptides have been the key recent contributions in this area. Advances in chemical polypeptide syntheses include new applications in solid and solution phase peptide coupling reactions as well as advances in the polymerization of a-amino acid-N-carboxyanhydride (NCA) monomers. The use of transition metal initiators in NCA polymerizations has allowed the preparation of very well defined homopolypeptides and may lead to facile routes into peptide block copolymer materials. The presence of stable, chiral structural elements in polypeptides results in self-assembly into ordered films, composites, and liquid crystals. If their sequences are designed and constructed properly, artificial polypeptides have considerable potential for use in construction of artificial tissues and implants, ordered inorganidorganic composites, and in medical diagnostics and biosensors

The reactions of (NH4)2Ce(N03)6 (CAN) with 2-8 equiv of NaOCMe, in THF and in tert-butyl alcohol have been studied. A series of ceric alkoxide complexes of general formula Ce(OCMe,),(NO,)b(solvent),"d ( a = 1-6; b = 0-3; c = 2, 4; d = 0, 2; a + b = 4 + 6) have been identified as well as Ce2(0CMe3)9Na and Ce3(OCMe3)lo0. Interconversion of these complexes by treatment with NaOCMe, or NH4N03 has also been studied. CAN reacts with 3 equiv of NaOCMe, in THF to form Ce-(OCMe,)(NO3),(THF), (1). In tert-butyl alcohol this reaction forms the HOCMe, solvate Ce(OCMe,)(NO,),(HOCMe,), (1').1 reacts with 1 equiv of NaOCMe, and CAN reacts with 4 equiv of NaOCMe, to form Ce(OCMe3)2(N03)2(THF), (2). In tert-butyl alcohol solvent, 1' reacts with NaOCMe, to form Ce(OCMe3)2(N03)2(HOCMe ), (2'). 2' crystallizes from a concentrated toluene solution at -34 OC in space group Pi (No. 2; Ci) with a = 10.7548 (56) i, b = 11.0853 (49) A, c = 12.4403 (56) A, a = 72.760 (34)O, = 88.190 (39)O, y = 69.050 (35)O, V = 1318.0 (11) A', and Z = 2 for Ddd = 1.41 g cm-,.Least-squares refinement of the model based on 4935 observed reflections converged to RF = 7.7%. If each NO, ligand is taken to occupy just one coordination site, the structure of 2' is that of a distorted octahedron in which identical ligands are trans to each other. Ce(OCMe3),(NOo)(THF)2 (3) can be prepared from 2 or 2' and NaOCMe, or from CAN and 5 equiv of NaOCMe,. Ce(OCMe,),(THF), (4) is prepared from 3 and NaOCMe, or from CAN and 6 equiv of NaOCMe,. The reaction of 4 with 2 equiv of NaOCMe, or reaction of CAN with 8 equiv of NaOCMe, forms Ce(OCMe3)6Na2(THF)4 (5). 5 cr s t a k e s from dimethoxyethane (DME) at -34 OC as Ce (OCMe3)6Na,(DME)2 (5') in space group PnaZl with a = 20.5337 (36) i, b = 10.9557 (23) A, c = 19.4128 (38) A, V = 4367.1 (15) A', and Z = 4 for Dmld = 1.22 gLeast-squares refinement of the model based on 9092 observed reflections converged to RF = 4.9%. 5' contains a distorted-octahedral arrangement of OCMe, groups around cerium. Each sodium ion is coordinated by one DME ligand and a facial set of three OCMe, groups of the Ce(OCMe,)62-octahedron. The reaction of 4 with equiv of NaOCMe, forms Cez(OCMe3)gNa (6). Both 4 and 6 in toluene slowly form Ce,(OCMe3)lo0 (7). Complex 5 reacts with 5 equiv of NH4N03 to form 1 in quantitative yield.

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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.

Injectable hydrogels with tunable physiochemical and biological properties are potential tools for improving neural stem/progenitor cell (NSPC) transplantation to treat central nervous system (CNS) injury and disease. Here, we developed injectable diblock copolypeptide hydrogels (DCH) for NSPC transplantation that contain hydrophilic segments of modified l-methionine (Met). Multiple Met-based DCH were fabricated by post-polymerization modification of Met to various functional derivatives, and incorporation of different amino acid comonomers into hydrophilic segments. Met-based DCH assembled into self-healing hydrogels with concentration and composition dependent mechanical properties. Mechanical properties of non-ionic Met-sulfoxide formulations (DCH) were stable across diverse aqueous media while cationic formulations showed salt ion dependent stiffness reduction. Murine NSPC survival in DCH was equivalent to that of standard culture conditions, and sulfoxide functionality imparted cell non-fouling character. Within serum rich environments in vitro, DCH was superior at preserving NSPC stemness and multipotency compared to cell adhesive materials. NSPC in DCH injected into uninjured forebrain remained local and, after 4 weeks, exhibited an immature astroglial phenotype that integrated with host neural tissue and acted as cellular substrates that supported growth of host-derived axons. These findings demonstrate that Met-based DCH are suitable vehicles for further study of NSPC transplantation in CNS injury and disease models.