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Cell-penetrating peptides (CPPs) have been widely utilized as efficient molecular tools for the delivery of bioactive cargoes such as peptides, proteins, and genetic material. However, to improve their versatility as tools in biological environments, the resistance of CPPs to enzymatic degradation and their structural stability must be improved to achieve long-term efficacy. Here we designed and synthesized novel artificial CPPs, poly(LysAibXaa), containing periodic α-aminoisobutyric acid (Aib) and l-lysine by chemoenzymatic polymerization. Poly(LysAibAla) tended to form 3

A series of low fouling peptide self-assembled monolayers (SAMs) was developed to understand how the effects of subtle sequence alterations determine the properties of peptide-terminated SAMs and s...

Aminoisobutyric acid (Aib) oligomers are known to form racemic mixtures of enantiomeric left- and right-handed structures. The introduction of a chiral cap converts the enantiomeric structures into diastereomers that, in principle, afford spectroscopic differentiation. Here, we screen different C-terminal caps based on a model Aib dipeptide using double resonance laser spectroscopy in the gas phase to record IR and UV spectra of individual conformations present in the supersonic expansion: NH-benzyl (NHBn) as a reference structure because of its common use as a fluorophore in similar studies, NH- p-fluorobenzyl (NHBn-F), and α-methylbenzylamine (AMBA). For both the NHBn and NHBn-F caps, a single conformer is observed, with infrared spectra assignable to an enantiomeric pair of type II/II' β-turns in these molecules lacking a chiral center. The higher oscillator strength of the NHBn-F cap enabled UV-UV hole burning, not readily accomplished with the NHBn cap. The AMBA-capped structure, with its chiral center, produced two unique conformers, one of which was a nearly identical left-handed type II β-turn, while the minor conformer is assigned to a C7-C7 sequential double ring, which is an emergent form of a 27-ribbon. Although not observed, the type II' β-turn diastereomer, with opposite handedness, is calculated to be 11 kJ/mol higher in energy, a surprisingly large difference. This destabilization is attributed primarily to steric interference between the C-terminal acyl oxygen of the peptide and the chirality-inducing methyl of the AMBA group. Last, computational evidence indicates that the use of an N-terminal aromatic cap hinders the formation of a 310-helix in Ac-Aib2 dipeptides.

We designed and synthesized a C(2)-symmetric cyclic hexapeptide, cyclo(L-Leu-D-Leu-Aib)(2) (2), which contains L- and D-amino acids and achiral Aib residues. The conformation of 2 was analyzed in the crystalline state and in solution, which was a unique figure-eight-shaped conformation.

Reported is the synthesis of azo mutual prodrugs of the nonsteroidal anti-inflammatory agents (NSAIDs) 4-aminophenylacetic acid (4-APAA) or 5-aminosalicylic acid (5-ASA) with peptides, including an antibiotic peptide temporin analogue modified at the amino terminal by an α-aminoisobutyric acid (Aib) residue. These prodrugs are designed for colonic delivery of two agents to treat infection and inflammation by the bacterial pathogen Clostridium difficile .

The non-natural amino acids (R)- and (S)-2-amino-3-fluoro-2-methylpropanoic acid 5 and (R)- and (S)-3-fluoro-2-methyl-2-N-(methylamino)propanoic acid 8 were synthesized in shorter reaction sequences than in the original report starting from enantiomerically pure (S)- and (R)-α-methyl-serine, respectively. The reaction sequence provided the cyclic sulfamidate precursors for radiosynthesis of (R)- and (S)-[18F]5 and (R)- and (S)-[18F]8 in fewer steps than in the original report. (R)- and (S)-[18F]5 and(R)- and (S)-[18F]8 were synthesized by no-carrier-added nucleophilic [18F]fluorination in 52−66% decay-corrected yields with radiochemical purity over 99%. The cell assays showed that all four compounds were substrates for amino acid transport and enter 9L rat gliosarcoma cells in vitro at least in part by system A amino acid transport. The biodistribution studies demonstrated that in vivo tumor to normal brain ratios for all compounds were high with ratios of 20:1 to115:1 in rats with intracranial 9L tumors....

Solvent effects on the conformational preferences of homopolypeptides constituted by α-aminoisobutyric acid (polyAib) have been investigated coupling the polarizable continuum model (PCM) either to a quantum mechanical (PBE0/6-31G(d)) or to a molecular−mechanical (Amber) representation of the solute. The results allow a deeper insight into the influence of the solvent on the 310/α-helix equilibrium in polyAib and show that PCM/Amber is a useful tool to study the conformational preferences of large peptides in condensed phase. As a matter of fact, all the PCM/Amber results are close to their PCM/PBE0 counterparts, except for some underestimation of the absolute solvation energies in polar solvents.

The combination of transferred-echo double resonance (TEDOR) with rotational-echo double resonance (REDOR) has been used to measure an 8-A fluorine-carbon internuclear distance in a nine-residue fragment of the peptide antibiotic emerimicin. The fragment is 19 FCH 2 CO-Phe-MeA-MeA-[1- 13 C]MeA-[ 15 N]Val-Gly-Leu-MeA-MeA-OBzl (MeA=α-methylalanine or aminoisobutyric acid). The TEDOR part of this magic-angle-spinning, solid-state NMR experiment selects the 13 C label by its dipolar coupling to 15 N and suppresses the natural-abundance carbon background