Pseudoprolines: Targeting acis Conformation in a Mimetic of the gp120 V3 Loop of HIV-1

Wittelsberger, Angela; Keller, Michael; Scarpellino, Léonardo; Patiny, Luc; Acha‐Orbea, Hans; Mutter, Manfred

doi:10.1002/(sici)1521-3773(20000317)39:6<1111::aid-anie1111>3.0.co;2-d

Cited by 63 publications

(43 citation statements)

References 14 publications

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“…[24,25] The potential value of such derivatives in synthetic vaccine design has also been highlighted. [26] Here, we show that a cis-Xaa ± Pro geometry can be locked without modification of the proline residue through its incorporation into a designed cyclic peptide.…”

Section: Discussionmentioning

confidence: 84%

A New Family of β-Hairpin Mimetics Based on a Trypsin Inhibitor from Sunflower Seeds

et al. 2002

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The ability of proteases to regulate many aspects of cell function and defense accounts for the considerable interest in the design of novel protease inhibitors. There are many naturally occurring proteinaceous serine protease inhibitors, one of which is a 14 amino acid cyclic peptide from sunflower seeds that shows both sequence and conformational similarity with the trypsin-reactive loop of the Bowman-Birk family of serine protease inhibitors. This inhibitor adopts a beta-hairpin conformation when bound at the active site of bovine beta-trypsin. We illustrate here an approach to inhibitor design in which the beta hairpin from the naturally occurring peptide is transplanted onto a hairpin-inducing template. Two mimetics with the sequences RC*TKSIPPIC*F (where C*C* is a disulfide) and TKSIPPI are studied, each mounted onto a D-Pro-L-Pro template. NMR studies revealed a well-defined beta-hairpin conformation for each mimetic in aqueous solution; this conformation is closely related to the trypsin-bound conformation of the natural inhibitor and includes a cis-Ile-Pro peptide bond. Both mimetics inhibit trypsin in the mid nanomolar range. An alanine scan revealed the importance for inhibitory activity of the specificity-determining Lys residue and of the first but not the second Pro residue in the IPPI motif. Since these hairpin mimetics can be prepared by parallel combinatorial synthesis, this family of molecules may be a useful starting point for the discovery of other biologically or medicinally useful serine protease inhibitors.

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Section: Discussionmentioning

confidence: 84%

A New Family of β-Hairpin Mimetics Based on a Trypsin Inhibitor from Sunflower Seeds

et al. 2002

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“…an α-aminoisobutyric (Aib) residue], by side-chain cross-linking or "stapling", and the use of helix caps and hydrogen bond surrogates. Some of these approaches have been explored already in vaccine design efforts, for example, the use of Aib residues to favour helical turns, hydrazone crosslinks as hydrogen bond surrogates, Freidinger-like lactams and pseudoprolines to stabilize turns, and cross-linked side-chains to stabilize helical epitopes [158][159][160][161][162][163][164][165]. β-Hairpin mimetics might also be very useful in synthetic vaccine design.…”

Section: Epitope Mimeticsmentioning

confidence: 99%

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Klein

Templeton

Schwenk

2014

Pure and Applied Chemistry

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This report discusses the history and mechanisms of vaccination of humans as well as the engineering of therapeutic antibodies. Deeper understanding of the molecular interactions involved in both acquired and innate immunity is allowing sophistication in design of modified and even synthetic vaccines. Recombinant DNA technologies are facilitating development of DNA-based vaccines, for example, with the recognition that unmethylated CpG sequences in plasmid DNA will target Toll-like receptors on antigen-presenting cells. Formulations of DNA vaccines with increased immunogenicity include engineering into plasmids with "genetic adjuvant" capability, incorporation into polymeric or magnetic nanoparticles, and formulation with cationic polymers and other polymeric and non-polymeric coatings. Newer methods of delivery, such as particle bombardment, DNA tattooing, electroporation, and magnetic delivery, are also improving the effectiveness of DNA vaccines. RNA-based vaccines and reverse vaccinology based on gene sequencing and bioinformatic approaches are also considered. Structural vaccinology is an approach in which the detailed molecular structure of viral epitopes is used to design synthetic antigenic peptides. Virus-like particles are being designed for vaccine deliveries that are based on structures of viral capsid proteins and other synthetic lipopeptide building blocks. A new generation of adjuvants is being developed to further enhance immunogenicity, based on squalene and other oil-water emulsions, saponins, muramyl dipeptide, immunostimulatory oligonucleotides, Toll-like receptor ligands, and lymphotoxins. Finally, current trends in engineering of therapeutic antibodies including improvements of antigen-binding properties, pharmacokinetic and pharmaceutical properties, and reduction of immunogenicity are discussed. Taken together, understanding the chemistry of vaccine design, delivery and immunostimulation, and knowledge of the techniques of antibody design are allowing targeted development for the treatment of chronic disorders characterized by continuing activation of the immune system, such as autoimmune disorders, cancer, or allergies that have long been refractory to conventional approaches.

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“…[3] More recently, the YPro concept was extended to targeting cis-amide bonds in biologically relevant recognition processes. [4] Up to now, the incorporation of YPro systems into peptide backbones was achieved by preforming the corresponding YPro building blocks according to Scheme 1 and subsequently coupling them to the peptide chain. Here, we explore the direct incorporation of pseudoprolines into complex peptide structures using the example of cyclosporin C (CsC).…”

Section: Introductionmentioning

confidence: 99%

Pseudoprolines (Pro) in Drug Design: Direct Insertion of Pro Systems into Cyclosporin C

et al. 2000

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The insertion of acetals that exhibit variable structural features into complex peptides such as cyclosporin C (CsC) results in oxazolidine derivatives (pseudoprolines, psiPro) of tailored physico-chemical and biological properties. N,O-Acetalation of the 2-threonine hydroxyl group and the preceding amide nitrogen of CsC is achieved by treating the molecule with a number of both arylated and non-arylated dimethyl acetals. The psiPro-containing CsC derivatives exhibit enhanced conformational backbone rigidity, as suggested by analytical HPLC, NMR spectroscopy and by kinetic measurements on binding with their receptor protein cyclophilin A (CypA) that were not time-dependent. IC50 values for calf-thymus CypA were obtained by kinetic evaluation of its cis-->trans isomerase activity. The choice of the para-substituted aryl dimethyl acetals allows the inhibitory properties of the corresponding derivatives to be modulated to either prodrugs or moderately strongly binding cyclosporin C derivatives.

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Pseudoprolines: Targeting acis Conformation in a Mimetic of the gp120 V3 Loop of HIV-1

Cited by 63 publications

References 14 publications

A New Family of β-Hairpin Mimetics Based on a Trypsin Inhibitor from Sunflower Seeds

A New Family of β-Hairpin Mimetics Based on a Trypsin Inhibitor from Sunflower Seeds

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Pseudoprolines (Pro) in Drug Design: Direct Insertion of Pro Systems into Cyclosporin C

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