Self-Promoted Glycosylation of Carbamoylated Peptides on Solid Phase.

Self-promoted glycosylations with trichloroacetimidate glycosyl donors are demonstrated on solid-phase-anchored peptides orthogonally deprotected and tosylcarbamoylated on the side-chains of cysteine and serine, respectively. The donor scope included glucosyl as well as mannosyl trichloroacetimidates, carrying benzyl, acetyl, or isopropylidene protecting groups. Isopropylidene groups were found to be removed under the acidic conditions used for release of the neoglycopeptides from the solid support, yielding neoglycopeptides with unprotected hydroxyl groups. Glycosylation of a peptide containing a carbamoylated tyrosine was attempted as well, but the desired neoglycopeptide could not be synthesized due to thermal instability of the carbamate.

Hydrodynamic Control of Alzheimer Aß Fibrillation with Glucosaminic Acid Containing Click-Cyclized ß-Bodies.

It is well established that the dynamic hydration shell plays a vital role in macromolecular functions such as protein-ligand, protein-protein, protein-DNA, and protein-lipid interactions. Here we investigate how the water modality affects conformational changes, solubility, and motion of fibrillar proteins. The hypothesis is that the introduction of a poly hydroxyl amino acid would increase solvation of the fibril forming peptides, preventing their misfolding and aggregation. For the amyloid ß (Aß) peptide, which is considered to be connected with nervous system diseases, including dementia and cognitive decline in Alzheimer's disease, the formation of ß-sheet fibrils always occurs with a conformational change and a decrease in the dynamic hydration shell around Aß(1-42). We present novel cyclic d-amino acid peptides that effectively inhibit fibrillation through affecting the dynamic hydration shell of Aß(1-42) in vitro. Using de novo design within the software Molecular Operating Environment (MOE), five different peptides that recognize Alzheimer's fibrils were designed and synthesized. Three of them were cyclic all-d-amino acid peptides incorporating the same polyhydroxy building block derived from d-glucosaminic acid (GA). One peptide was the parent cyclic all d-amino acid inhibitor with no GA incorporated, and another was an all l-amino acid linear fibrillation inhibitor. The GA-containing peptides were found to show significantly improved inhibition of Aß(1-42) aggregation. The inhibition was dramatically improved by the synergistic application of two GA peptides targeting each end of the growing fibril. The present study may facilitate future developments of intervention strategies for Alzheimer's disease and similar neurodegenerative diseases.

Radiolabeled albumin through SNAr of cysteines as a potential pretargeting theranostic agent.

Human serum albumin (HSA) has been shown to be a promising tumor targeting vector and target for generating theranostics by bioconjugation. Unstable chemical conjugation to HSA via a cysteine (Cys34) by reversible Michael additions is most commonly applied for this purpose. Herein, we describe utilization of our recently developed site-selective irreversible SNAr conjugation to Cys34 using perfluorobenzene sulfonyl derivatives to introduce a trans-cyclooctene (TCO) handle. The TCO could then be bioorthogonally ligated within minutes through an inverse-electron demand Diels-Alder reaction (IEDDA) to tetrazines (Tzs) containing a radionuclide. The methodology opens up a wide range of chemistries including pretargeting, 'click-to-release' tumor selective drug delivery or ultra-fast and complete conjugation of any drug. The proof-of-principle study demonstrated that the conjugation chemistry is feasible, robust and easy to carry out, being promising for pretargeted imaging and therapy studies as well as selective drug delivery using HSA.

Tuning Peptide Structure and Function through Fluorobenzene Stapling.

Cyclic peptides are promising next-generation therapeutics with improved biological stability and activity. A catalyst-free stapling method for cysteine-containing peptides has been developed that enables fine-tuning of the macrocycle by using the appropriate regioisomers of fluorobenzene linkers. Stapling was performed on the unprotected linear peptide or, more conveniently, directly on-resin after peptide synthesis. NMR spectroscopy and circular dichroism studies demonstrate that the type of stapling can tune the secondary structures of the peptides. The method was applied to a set of potential agonists for melanocortin receptors, generating a library of macrocyclic potent ligands with ortho, meta or para relationships between the thioethers. Their small but significant differences in potency and efficacy demonstrate how the method allows facile fine-tuning of macrocyclic peptides towards biological targets from the same linear precursor.

C-Terminal lactamization of peptides.

Solid-phase synthesis of peptides (SPPS) with release through formation of C-terminal γ-, δ-, or ε-lactams is presented. The natural products ciliatamide A and C were synthesized in up to 90% yield. Peptides carrying C-terminal lactams were shown to possess increased bio-stability and comparable biological activity as compared to the parent non-lactamized peptide amides.