Redesigning Protein Function: Towards Synthetic Vaccines and MHC Mimetics

Template Assembled Synthetic Proteins (TASP) approach has been applied to mimic 3D-conformations of the hen egg white lysozyme antigen (HEL) and the major histocompatibility complex (MHC) and some of their biological properties

Toward the Design of Highly Efficient, Readily Accessible Peptide N-caps for the Induction of Helical Conformations

A series of novel peptide N-caps was designed with an emphasis on ease of synthesis and an abundance of hydrogen bond acceptors. Different scaffolds based on sugars, cyclic hydrocarbons, and amino acids are developed with a variety of hydrogen bond acceptors including esters, carboxyls, amides and a sulfonic acid. The efficient use in solid-phase peptide synthesis was demonstrated by incorporating the N-caps to a resin-bound model peptide. Their differential helix nucleating power in aqueous buffer was determined by CD studies. Increases in peptide helicity to a significant extent are observed, leading to a discussion of N-capping efficiency versus ease of synthesis. The potential of the elaborated N-caps for the reversal of β-sheet to α-helix conformations in the context of fibrillogenesis is discusse

Protein de novo Design

The ultimate goal in protein de novo design is the construction of artificial proteins exhibiting tailor-made structural and functional properties. To create native-like macromolecules in copying nature's way has proven to be difficult because the mechanism of folding in its complexity has yet to be unraveled. In order to bypass the well-known folding problem, we have developed the concept of template assembled synthetic proteins (TASP); this meanwhile widely accepted strategy uses topological templates as 'built-in' devices for the induction of well-defined folding topologies. Progress in synthetic strategies, e.g., chemoselective ligation methods and orthogonal protection techniques open the way for the design of more complex TASP molecules featuring functional properties such as membrane channels, vaccines, catalysts, receptors, or ligands

Engineering of zinc finger and MHC motifs to locked-in tertiary folds

The assembly of helical and β-sheet peptide blocks containing reactive chain ends results inhighly branched chain architectures (‘locked-in folds') mimicking native tertiary structures.This molecular kit strategy allows to bypass the protein folding problem in protein de novodesign and gives access to protein mimetics of high thermodynamic stability. The validity ofthis concept is exemplified for the design and synthesis of locked-in folds mimicking the zincfinger and MHC folding motif

Switch-peptides: design and characterization of controllable super-amyloid-forming host-guest peptides as tools for identifying anti-amyloid agents

Several amyloid-forming proteins are characterized by the presence of hydrophobic and highly amyloidogenic core sequences that play critical roles in the initiation and progression of amyloid fibril formation. Therefore targeting these sequences represents a viable strategy for identifying candidate molecules that could interfere with amyloid formation and toxicity of the parent proteins. However, the highly amyloidogenic and insoluble nature of these sequences has hampered efforts to develop high-throughput fibrillization assays. Here we describe the design and characterization of host-guest switch peptides that can be used for in vitro mechanistic and screening studies that are aimed at discovering aggregation inhibitors that target highly amyloidogenic sequences. These model systems are based on a host-guest system where the amyloidogenic sequence (guest peptide) is flanked by two beta-sheet-promoting (Leu-Ser)(n) oligomers as host sequences. Two host-guest peptides were prepared by using the hydrophobic core of Abeta comprising residues 14-24 (HQKLVFFAEDV) as the guest peptide with switch elements inserted within (peptide 1) or at the N and C termini of the guest peptide (peptide 2). Both model peptides can be triggered to undergo rapid self-assembly and amyloid formation in a highly controllable manner and their fibrillization kinetics is tuneable by manipulating solution conditions (for example, peptide concentration and pH). The fibrillization of both peptides reproduces many features of the full-length Abeta peptides and can be inhibited by known inhibitors of Abeta fibril formation. Our results suggest that this approach can be extended to other amyloid proteins and should facilitate the discovery of small-molecule aggregation inhibitors and the development of more efficacious anti-amyloid agents to treat and/or reverse the pathogenesis of neurodegenerative and systemic amyloid diseases

Designing novel proteins

A review with 53 refs. [on SciFinder (R)

Under the influence of phi and psi

A review. Topics include pseudo-prolines (YPro) as a solubilizing, structure-disrupting protection technique in peptide synthesis and the concept of Template-Assembled-Synthetic Proteins (TASP). [on SciFinder (R)

Peptidomimetics for Bridging Structure and Function: Pseudo-Prolines (ΨPro) in Peptide Synthesis, Molecular Recognition, and Drug Design

The central issue of bioorganic chemistry is to unravel the structural and functional complexity of living systems by designing synthetic models that mimic essential features of biomolecules. In view of the expected exponential growth of knowledge within the next decade about structure–activity relationships in bioactive compounds as well as about mechanisms of molecular recognition in cellular communication, conversion of the design of therapeutically relevant molecules currently provides one of the most fascinating challenges for synthetic organic chemistry. Independent of evolutionary restrictions in creating the molecules of life, the chemist may even go a step further in extending Nature's pool of biomolecules for studying biochemical processes. One way of doing this is illustrated in the present article. Taking proline (Pro) as a unique building block in peptides and proteins, we have explored its particular role in a variety of biological processes by tuning its intrinsic structural and functional properties using readily accessible proline mimetics ('pseudoprolines', ΨPro). In enhancing and extending well-known Pro effects, i.e. cis-trans amide bond isomerization, conformational restriction or specific receptor interaction, ΨPro derivatives are useful as synthetic tools in molecular recognition studies and for modulating the physicochemical, pharmacokinetic and biological properties of peptide and protein ligands. Selected examples from our ongoing research program in peptidomimetic chemistry demonstrate that synthetic tools can substantially contribute to our understanding of fundamental principles underlying biological processes and serve as a first step in accessing molecules of therapeutic relevance

Switch-peptides as tool for the study of fibrillogenesis

The invention discloses a method for the manuf. of a peptidic folding precursor (switch-peptide) stable and sol. at physiol. conditions, derived from a peptide having a potential for self-assembling and fibrillogenesis. Another object of the invention is to provide a tool for the quant., controlled in vitro study of fibrillogenesis and its inhibition of peptides involved in degenerative diseases. Prepn. of peptides is described