A comparative protease stability study of synthetic macrocyclic peptides that mimic two endocrine hormones

Ferrie, John J.; Gruskos, Jessica J.; Goldwaser, Ari L.; Decker, Megan E.; Guarracino, Danielle A.

doi:10.1016/j.bmcl.2012.12.041

Cited by 25 publications

(30 citation statements)

References 24 publications

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“…All of the head‐to‐tail cyclic peptides, and the linear control, were synthesized using standard solid‐phase peptide synthesis techniques (see Experimental Section) . The Q‐peptide used as a control and comparator in our studies, representing the superior peptide of those originally found in the literature, was purchased and synthesized by Anaspec.…”

Section: Resultsmentioning

confidence: 99%

“…The final peptide was obtained upon cleavage from the bead, resulting in an asparagine residue in the place where the linkage to Rink resin had occurred. Each synthesized peptide was purified to ≥95 % purity by analytical reverse phase high performance liquid chromatography (RP‐HPLC) and identified by mass with a range of 0.017–0.032 % error using liquid chromatography mass spectrometry (LC–MS; see Supporting Information) …”

Section: Resultsmentioning

confidence: 99%

“…Each sample was incubated at 37 °C for a set amount of time (30 min, 1 h, 2 h, or 6 h) and then treated with the appropriate “stop” solution (generally a large change in pH) to halt the reaction. All samples were examined using LC–MS and the percent degradation calculated by comparing the peak representing the peptide incubated in buffer alone versus in the presence of the enzyme (see Supporting Information) …”

Section: Resultsmentioning

confidence: 99%

“…All of the head-to-tail cyclic peptides, and the linear control, were synthesized using standard solid-phasep eptide synthesis techniques (see ExperimentalS ection). [14][15][16] The Q-peptide used as ac ontrol and comparator in our studies, representing the superior peptide of those originally found in the literature, was purchased and synthesized by Anaspec. In summary,f or the cyclic peptides ynthesis an Fmoc-protected aspartate residue with no side chain protection and an allyl C-terminal protecting group was first loaded ontoR ink resin, followed by repeated synthetic steps to the final glycine residue.U sing ap alladium catalyst and phenylsilane, the allyl group was removed and the N-and C-termini coupled together to form the cycle.…”

Section: Peptided Esign and Synthesismentioning

confidence: 99%

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Head‐to‐Tail Cyclic Peptide Inhibitors of the Interaction between Human von Willebrand Factor and Collagen

et al. 2017

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The development of peptide-based therapeutics is on the rise, with macrocyclic compounds providing the added stability and drug-like characteristics sought after. Currently, therapies and preventatives for pathogenic thrombosis target platelet interactions at the site of the clot and have many complications. Herein we describe novel cyclic peptides as moderate inhibitors of the protein-protein interaction between von Willebrand factor (vWF) and collagen that initiates blood clot formation. We based our designs on two known disulfide-containing, peptide-based inhibitors of the vWF-collagen interaction. Replacing the disulfide with a head-to-tail cyclization strategy confers remarkable stability to the peptides when treated with a panel of proteases. Our peptides also showed moderate activity in our developed fluorescently linked immunosorbent assay (FLISA), similar to the most active disulfide-containing peptide. These peptides provide a springboard for future advances in exceptionally stable, active cyclic peptides as drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Peptided Esign and Synthesismentioning

confidence: 99%

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Head‐to‐Tail Cyclic Peptide Inhibitors of the Interaction between Human von Willebrand Factor and Collagen

et al. 2017

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“…Other desirable pharmacological properties introduced by the macrocycle include increased metabolic stability, cellular uptake, and tissue distribution. 20,21 The size and position of the macrocycle was based on the natural product TMC-95. The inhibitors 7 and 8 incorporate a para−meta biphenyl ether linkage that results in a 17-membered macrocycle, mimicking the ring size and structure of TMC-95A while avoiding the synthetic challenges associated with the oxidized tryptophan and biaryl linkage.…”

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confidence: 99%

Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome

Wilson

Meininger

Strater

et al. 2016

ACS Med. Chem. Lett.

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This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC-95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inhibited in the low nanomolar range and proved to be selective for the proteasome over other serine and cysteine proteases, particularly when compared to linear analogues with similar amino acid sequences. In HeLa cells, both macrocycles efficiently inhibited activation of nuclear factor-κB (NF-κB) transcription factor by blocking proteasomal degradation of the inhibitor protein IκBα after cytokine stimulation. Due to their covalent mechanism of binding these compounds represent a 1000-fold increase in inhibitory potency over previously reported noncovalently binding TMC-95 analogues. Molecular modeling of the macrocyclic peptides confirms the preference of the large S 3 pocket for large, hydrophobic residues and the ability to exploit this to improve selectivity of proteasome inhibitors.

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Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

et al. 2017

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Unsere sich stetig erweiternden Kenntnisse über biologische Systeme haben eine Vielzahl an hoch interessanten neuen biologischen Zielstrukturen aufgedeckt, deren Modulation möglicherweise neuartige Therapiemöglichkeiten für viele Krankheiten erschließt. Diese Angriffspunkte umfassen insbesondere Protein‐Protein‐ und Protein‐Nukleinsäure‐Wechselwirkungen, die jedoch durch klassische niedermolekulare Substanzen oftmals nicht adressierbar sind. Andere Substanzklassen oder Modalitäten werden daher benötigt, um diese Ziele anzuvisieren. Einige akademische Forschungsgruppen und pharmazeutische Unternehmen greifen daher zunehmend das Konzept der so genannten “neuen Modalitäten” auf. Dieser Aufsatz definiert erstmals diesen Begriff, der neuartige Peptidgerüststrukturen, Oligonukleotide, Hybride, molekulare Konjugate sowie auf neuartige Weise eingesetzte, klassische niedermolekulare Verbindungen berücksichtigt. Wir stellen die repräsentativsten Beispiele dieser Modalitäten vor, die auf große Bindungsoberflächen, wie sie in Protein‐Protein‐Wechselwirkungen vorkommen, sowie auf zentrale biologische Zellregulationsvorgänge abzielen.

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A comparative protease stability study of synthetic macrocyclic peptides that mimic two endocrine hormones

Cited by 25 publications

References 24 publications

Head‐to‐Tail Cyclic Peptide Inhibitors of the Interaction between Human von Willebrand Factor and Collagen

Head‐to‐Tail Cyclic Peptide Inhibitors of the Interaction between Human von Willebrand Factor and Collagen

Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

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