Peptide Bond Isosteres:  Ester or (<i>E</i>)-Alkene in the Backbone of the Collagen Triple Helix

Jenkins, Cara L.; Vasbinder, Melissa M.; Miller, Scott J.; Raines, Ronald T.

doi:10.1021/ol050780m

Cited by 84 publications

(98 citation statements)

References 26 publications

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“…General Protocol: The appropriate Boc-Xaa-Gly-OBn derivative (11) or (16) 79 (52.5 mmol) was dissolved in 4 N HCl in dioxane (700 mL) under Ar(g) and stirred for 2 h. The resulting solution was concentrated under reduced pressure, dried under high vacuum and the residue dissolved in anhydrous CH 2 Cl 2 (800 mL) under Ar(g). The appropriate 4-chloroproline derivative (7) or (8) …”

Section: Pybrop Couplingsmentioning

confidence: 99%

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

2007

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Collagen is an abundant, triple-helical protein comprising three strands of the repeating sequence: Xaa-Yaa-Gly. (2S)-Proline and (2S,4R)-4-hydroxyproline (Hyp) are common in the primary structure of collagen. Here, we use nonnatural proline derivatives to reveal determinants of collagen stability. Specifically, we report high-yielding syntheses of (2S,4S)-4-chloroproline (clp) and (2S, 4R)-4-chloroproline (Clp). We find that the crystal structure of Ac-Clp-OMe is virtually identical to that of Ac-Hyp-OMe. In contrast, the conformational properties of Ac-clp-OMe are similar to those of Ac-Pro-OMe. Ac-Clp-OMe has a stronger preference for a trans amide bond than does Ac-ProOMe, whereas Ac-clp-OMe has a weaker preference. (Pro-Clp-Gly) 10 forms triple helices that are significantly more stable than those of (Pro-Pro-Gly) 10 . Triple helices of (clp-Pro-Gly) 10 have stability similar to those of (Pro-Pro-Gly) 10 . Unlike (Pro-Clp-Gly) 10 and (clp-Pro-Gly) 10 , (clpClp-Gly) 10 does not form a stable triple helix, presumably due to a deleterious steric interaction between proximal chlorines on different strands. These data, which are consistent with previous work on 4-fluoroprolines and 4-methylprolines, support the importance of stereoelectronic and steric effects in the stability of the collagen triple helix and provide another means to modulate that stability.

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Section: Pybrop Couplingsmentioning

confidence: 99%

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

2007

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“…Likewise, proteins containing a cis-peptide bond can be stabilized by constrained amides or isosteres (21)(22)(23). The utility of these substitutions is limited, however, by the difficulty of modifying the backbone of proteins as well as concomitant effects on structure and function (24)(25)(26)(27).…”

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confidence: 99%

Stereoelectronic and steric effects in side chains preorganize a protein main chain

Shoulders¹,

Satyshur²,

Forest³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Preorganization is shown to endow a protein with extraordinary conformational stability. This preorganization is achieved by installing side-chain substituents that impose stereoelectronic and steric effects that restrict main-chain torsion angles. Replacing proline residues in ðProProGlyÞ 7 collagen strands with 4-fluoroproline and 4-methylproline leads to the most stable known triple helices, having T m values that are increased by >50°C. Differential scanning calorimetry data indicate an entropic basis to the hyperstability, as expected from an origin in preorganization. Structural data at a resolution of 1.21 Å reveal a prototypical triple helix with insignificant deviations to its main chain, even though 2∕3 of the residues are nonnatural. Thus, preorganization of a main chain by subtle changes to side chains can confer extraordinary conformational stability upon a protein without perturbing its structure.collagen triple helix | nonnatural amino acid | preorganization | protein stability | x-ray crystallography T he three-dimensional structures of proteins are stable because of a delicate balance of forces (1). Increases in the conformational stability of a protein-desirable in many contexts (2)-can be realized by enhancing the hydrophobic effect (3, 4), introducing or shielding a hydrogen bond (5) or electrostatic interaction (6-8), or introducing a disulfide crosslink (9-11) or metal ion-binding site (12). These strategies are often frustrated by enthalpy-entropy compensation, whereby enthalpic stabilization is offset entirely by entropic destabilization, or vice versa (13). Moreover, the strategies often lack subtlety and can lead to a misshapen and hence dysfunctional protein.As elaborated by Cram (14), the principle of preorganization states that, "the more highly hosts and guests are organized for binding and low solvation prior to their complexation, the more stable will be their complexes." In a typical manifestation, a conformational constraint is imposed upon a receptor or ligand during its chemical synthesis. This principle can also yield biopolymers with increased conformational stability (Fig. 1). For example, the stability of a DNA duplex correlates with the helicity of its single strands (15, 16), and a bicyclic ("locked") derivative of ribose enhances that stability (17, 18). The stability of β-turns within protein structures can be increased by incorporating Dproline (19) and certain β-amino acids (20) that bias the conformations occupied by the unfolded polypeptide. Likewise, proteins containing a cis-peptide bond can be stabilized by constrained amides or isosteres (21-23). The utility of these substitutions is limited, however, by the difficulty of modifying the backbone of proteins as well as concomitant effects on structure and function (24-27).We suspected that alterations to proline residues could provide a particularly incisive means to preorganize the conformation of a polypeptide chain. In classic work, Matthews and coworkers substituted proline, which is the least flexible residu...

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“…It was revealed that vaccine efficacy does not only depend on the biochemical composition of the immunogens (vaccine constructs) but also their morphological properties, such as particle size, plays a role in the induction of immune response [50,51]. There are reports that vaccines delivered in the form of particulate: (i) are likely to be uptake by APCs for immune processing [52]; (ii) protects antigen from enzymatic degradation; and (iii) large particulates can act as depots (i.e.…”

Section: Formulation Into Nanoparticlesmentioning

confidence: 99%

“…There are reports that vaccines delivered in the form of particulate: (i) are likely to be uptake by APCs for immune processing [52]; (ii) protects antigen from enzymatic degradation; and (iii) large particulates can act as depots (i.e. trapping antigen and therefore slowly presents the antigen to immune cells) [53] while smaller ones (<200 nm) are readily transported through the lymphatic system [51,52], where many immune cells reside. These discoveries resulted to growing interest into the development of vaccines with well-defined particle sizes [33].…”

Section: Formulation Into Nanoparticlesmentioning

confidence: 99%

“…Peptide bonds can be replaced by mimicking functional groups (e.g., ester) [49,50]; however, not all of them, when incorporated in the sequence, are able to maintain secondary structure of the peptide (e.g., alkene) [51]. These facts prompted special interest in the application of triazole moiety for this purpose.…”

Section: Structural Studies Of Amide Bond and 14-disubstituted Triazolementioning

confidence: 99%

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The development of peptide-based subunit vaccines against Streptococcus pyogenes, Necator americanus and Schistosome mansoni

Fuaad¹

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Immunization via the use of whole pathogen (or its biological component) has been one of the most successful public health interventions. Historically, Edward Jenner pioneered the modern vaccination in the late 17 th century and since; vaccine research has been evolving rapidly. The practice of conventional vaccination, with attenuated or killed pathogen, was accepted worldwide and with this strategy, protections against many diseases were established. Nevertheless, not all diseases can be prevented via the conventional vaccination approach. For example, there is no vaccine against group A streptococcus (GAS), hookworm or schistosome infection, although recent statistics shows that these diseases affect almost a billion people worldwide (i.e. high demand for vaccines). The conventional vaccination via the use of weakened or killed GAS pathogen could result in the development of fatal autoimmune diseases (i.e. rheumatic fever and rheumatic heart disease), while vaccination using whole hookworm or schistosome parasite failed to develop protection in human, despite these vaccines were successful in animal (murine and/or canine) models. Therefore, synthetic vaccination approach via the use of minimal pathologic component (subunit peptide) necessary to stimulate immune response has the potential to address the drawbacks of using conventional vaccination approach. However, as peptides are poor immunogens on their own, the approach necessitates the use of adjuvants (immunostimulant) or carrier molecules to boost the vaccines' immunogenicity.In this PhD research project, novel carrier systems/delivery platforms were utilized for the development of synthetic (subunit) vaccines against three pathogens: Streptococcus pyogenes (GAS), Necator americanus (hookworm) and Schistosoma mansoni (schistosome). Two types of acrylate polymers, linear-and dendritic-poly(t-butyl)acrylate (PtBA), were used for the GAS vaccine development project while the lipid core peptide (LCP) systems were used for the development of self-adjuvanting vaccines against hookworm and schistosome infections. This research work mainly involved the design of peptide epitope, the synthesis of the subunit peptide and the delivery platforms, the conjugation peptides to the delivery platforms and immunological evaluation of the vaccine candidates in (inbred) mice model.In summary:• The synthetic pathway to produce self-assembled polymer-peptide hybrid vaccines via copper catalysed azide-alkyne cycloaddition (CuAAC) reaction was established for the development of vaccine candidates against GAS. The candidates were able to form ii distinct nanoparticles with sizes of 500 nm and 20 nm, for the linear-and dendriticPtBA, respectively. The conjugates were able to stimulate IgG secretion against J14peptide after a single-dose immunization, without the use of additional adjuvant.• Vaccines that are able to stimulate the humoral response (production of neutralizing antibodies) are vital for the development of therapeutics against hookworm infection.Alternative ap...

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Peptide Bond Isosteres: Ester or (E)-Alkene in the Backbone of the Collagen Triple Helix

Cited by 84 publications

References 26 publications

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

4‐Chloroprolines: Synthesis, conformational analysis, and effect on the collagen triple helix

Stereoelectronic and steric effects in side chains preorganize a protein main chain

The development of peptide-based subunit vaccines against Streptococcus pyogenes, Necator americanus and Schistosome mansoni

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