scholarly journals Short Peptides with Uncleavable Peptide Bond Mimetics as Photoactivatable Caspase-3 Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 206
Author(s):  
Tim Van Kersavond ◽  
Raphael Konopatzki ◽  
Suravi Chakrabarty ◽  
Bernhard Blank-Landeshammer ◽  
Albert Sickmann ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Covalent Bond ◽  
Peptide Bond ◽  
Covalent Modification ◽  
Chemical Probes ◽  
Design And Synthesis ◽  
Peptide Aldehydes ◽  
Protease Substrate

Chemical probes that covalently interact with proteases have found increasing use for the study of protease function and localization. The design and synthesis of such probes is still a bottleneck, as the strategies to target different families are highly diverse. We set out to design and synthesize chemical probes based on protease substrate specificity with inclusion of an uncleavable peptide bond mimic and a photocrosslinker for covalent modification of the protease target. With caspase-3 as a model target protease, we designed reduced amide and triazolo peptides as substrate mimetics, whose sequences can be conveniently constructed by modified solid phase peptide synthesis. We found that these probes inhibited the caspase-3 activity, but did not form a covalent bond. It turned out that the reduced amide mimics, upon irradiation with a benzophenone as photosensitizer, are oxidized and form low concentrations of peptide aldehydes, which then act as inhibitors of caspase-3. This type of photoactivation may be utilized in future photopharmacology experiments to form protease inhibitors at a precise time and location.

scholarly journals The 9-Fluorenylmethoxycarbonyl (Fmoc) Group in Chemical Peptide Synthesis – Its Past, Present, and Future

2020 ◽  
Vol 73 (4) ◽  
pp. 271 ◽  
Author(s):  
Wenyi Li ◽  
Neil M. O'Brien-Simpson ◽  
Mohammed Akhter Hossain ◽  
John D. Wade
Keyword(s):  
Chemical Synthesis ◽  
Peptide Synthesis ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Peptide Bond ◽  
Synthesis Methods ◽  
Protecting Group ◽  
Fmoc Group ◽  
The 1960S ◽  
The Many

The chemical formation of the peptide bond has long fascinated and challenged organic chemists. It requires not only the activation of the carboxyl group of an amino acid but also the protection of the Nα-amino group. The more than a century of continuous development of ever-improved protecting group chemistry has been married to dramatic advances in the chemical synthesis of peptides that, itself, was substantially enhanced by the development of solid-phase peptide synthesis by R. B. Merrifield in the 1960s. While the latter technology has continued to undergo further refinement and improvement in both its chemistry and automation, the development of the base-labile 9-fluorenylmethoxycarbonyl (Fmoc) group and its integration into current synthesis methods is considered a major landmark in the history of the chemical synthesis of peptides. The many beneficial attributes of the Fmoc group, which have yet to be surpassed by any other Nα-protecting group, allow very rapid and highly efficient synthesis of peptides, including ones of significant size and complexity, making it an even more valuable resource for research in the post-genomic world. This review charts the development and use of this Nα-protecting group and its adaptation to address the need for more green chemical peptide synthesis processes.

Evaluation of the Synthetic Product

2002 ◽  
Author(s):  
Gregory A. Grant
Keyword(s):  
Peptide Synthesis ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Side Reactions ◽  
Design And Synthesis ◽  
Synthetic Product ◽  
One Step ◽  
Evaluation Stage ◽  
And Performance ◽  
The One

In 1987, an article appeared in the International Journal of Peptide and Protein Research commemorating the 25th anniversary of the development of solid phase peptide synthesis (Barany et al., 1987). While that article dealt with many aspects of peptide synthesis, one statement in particular stands out as exemplifying the rationale for this chapter. It states: “No synthetic endeavor can be considered complete until the product has been adequately purified and subjected to a battery of analytical tests to verify its structure.” The characterization or evaluation of a synthetic peptide is the one step in its production and experimental utilization that will validate the experimental data obtained. Unfortunately, it is also the one step that many investigators all too often give too little attention. If the synthetic product, upon which the theory and performance of the experimental investigation is based, is not the intended product, the conclusions will be incorrect. Without proper characterization, the investigator will either have to be lucky, or be wrong. Worse yet, he or she will not know which is the case. Although today the synthesis of a given peptide is often considered routine, the product should never be taken for granted. Peptide synthesis chemistry, although quite sophisticated, is complex and subject to a variety of problems. These problems, which can manifest themselves as unwanted side reactions and decreased reaction efficiency, are subject to a variety of factors such as reagent quality, incompatible chemistries, instrument malfunctions, sequence specific effects, and operator error. Although every effort is made to eliminate their causes and to plan for potential problems in the design and synthesis steps, it is not always successful and the eventual outcome of a synthesis is not always predictable. One must never assume that the final product is the expected one until that has been proven to be the case. To do otherwise may seriously jeopardize the outcome of the research. Used and performed properly, the evaluation stage is where the fruits of the synthesis are scrutinized and the decision is made to use the peptide as intended, submit it to further purification, or resynthesize it and possibly change elements of the design or synthesis protocols.

Design and Synthesis of a Quenched Fluorogenic Peptide Substrate for Human Cytomegalovirus Proteinase

1995 ◽  
Vol 6 (4) ◽  
pp. 255-261 ◽  
Author(s):  
B.K. Handa ◽  
E. Keech ◽  
E.A. Conway ◽  
A. Broadhurst ◽  
A. Ritchie
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
Natural Substrate ◽  
Peptide Substrate ◽  
Protein Precursor ◽  
Design And Synthesis ◽  
Fluorogenic Peptide Substrate ◽  
Fluorogenic Peptide

A fluorogenic peptide substrate for HCMV proteinase was synthesized by solid-phase peptide synthesis. The amino acid sequence of this substrate is derived from the maturation cleavage site (M site) of the natural substrate, the assembly protein precursor. The minimum sequence for efficient cleavage requires at least seven residues (P4-P3′). A systematic modification of the peptide substrate was carried out to identify positions suitable for the introduction of the fluorescent donor and the quencher acceptor groups.

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