Improved solid phase synthesis of C-terminal peptide aldehydes

Fehrentz, Jean‐Alain; Paris, Marielle; Heitz, Annie; Velek, J.; Liu, Chuan‐Fa; Winternitz, F.; Martinez, Jean

doi:10.1016/0040-4039(95)01646-y

Cited by 85 publications

(43 citation statements)

References 18 publications

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“…Peptide aldehydes have been established as inhibitors of several classes of proteolytic enzymes [11] including aspartic proteases, [12,13] cysteine proteases, [14,15] and serine proteases. [16,17] Despite their reactivity as electrophiles, a therapeutic potential has also been attributed to peptide aldehydes.…”

Section: Introductionmentioning

confidence: 99%

“…A prerequisite for targeting SARS-CoV M pro with peptide aldehydes was a reliable and robust protocol for the parallel synthesis and library preparation of these compounds. The published peptide aldehyde synthesis protocols show limitations in yield, purity, and the ease of product isolation, [11,19,20] so we decided to develop a technique for the synthesis of peptide aldehyde libraries based on an N-tert-butyl oxycarbonyl (Boc-) protected oxazolidine linker. Various polar and nonpolar polymer supports were assessed to determine the optimimum linker-resin combination.…”

Section: Introductionmentioning

confidence: 99%

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An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV M^pro) Inhibitors

et al. 2006

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A method for the parallel solid-phase synthesis of peptide aldehydes has been developed. Protected amino acid aldehydes obtained by the racemization-free oxidation of amino alcohols with Dess-Martin periodinane were immobilized on threonyl resins as oxazolidines. Following Boc protection of the ring nitrogen to yield the N-protected oxazolidine linker, peptide synthesis was performed efficiently on this resin. A peptide aldehyde library was designed for targeting the SARS coronavirus main protease, SARS-CoV M(pro)(also known as 3CL(pro)), on the basis of three different reported binding modes and supported by virtual screening. A set of 25 peptide aldehydes was prepared by this method and investigated in inhibition assays against SARS-CoV M(pro). Several potent inhibitors were found with IC(50) values in the low micromolar range. An IC(50) of 7.5 muM was found for AcNSTSQ-H and AcESTLQ-H. Interestingly, the most potent inhibitors seem to bind to SARS-CoV M(pro) in a noncanonical binding mode.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV M^pro) Inhibitors

et al. 2006

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“…We first approached the synthesis of WK 18 LLnV-vinyl ester (ve), by releasing the fully protected WK 18 LLnV-aldehyde from the Weinreb amide resin with LAH, followed by its direct conversion to the vinyl ester using a Horner-Wadsworth-Emmons reaction (19,(24)(25)(26). This strategy was successful, but only afforded 1% yields of the desired WK 18 LLnV-ve and proved difficult to optimize.…”

Section: Resultsmentioning

confidence: 99%

A Novel Class of Intrinsic Proteasome Inhibitory Gene Transfer Peptides

Martin

Rice

2007

Bioconjugate Chem.

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Proteasomes are multisubunit enzymes responsible for the degradation of many cytosolic proteins. The inhibition of the proteasome has been the subject of intense interest in the development of drug therapies. We have previously demonstrated that simultaneous administration of a tripeptide aldehyde proteasome inhibitor (MG115 or MG132) with a peptide (Cys-Trp-Lys 18 ) DNA condensate boosted gene expression by 30-fold in cell culture. In the present study, we have developed a convergent synthesis to allow the incorporation of a proteasome inhibitor tripeptide into the C-terminal end of a gene delivery peptide. The resulting peptides formed DNA condensates that mediated a 100-fold enhancement in gene expression over a control peptide lacking all or part of the tripeptide inhibitor. Gene transfer peptides possessing intrinsic proteasome inhibitors were also found to be non-toxic to cells in culture. These results suggest that intrinsic proteasome inhibition may also be used to boost the efficiency of peptide mediated nonviral gene delivery systems in vivo.

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“…After coupling the modified Phe (3), the resin bound tetrapeptides 5 and 6 were cyclized according to the procedure developed by Boger et al 28 The macrocycle was cleaved from the resin using lithium aluminum hydride to generate a peptide aldehyde from a Weinreb amide. 31 For proof of concept we also prepared linear analogue 9 (Cbz-Phe-Phe(4-OMe)-Phe-Leu-H) with an amino acid sequence similar to compound 8. The linear tetrapeptide 9 was synthesized by solid phase approach on a Weinreb amide with Fmoc-protection chemistry (not shown in scheme).…”

Section: Acs Medicinal Chemistry Lettersmentioning

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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Improved solid phase synthesis of C-terminal peptide aldehydes

Cited by 85 publications

References 18 publications

An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV M^pro) Inhibitors

An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV M^pro) Inhibitors

A Novel Class of Intrinsic Proteasome Inhibitory Gene Transfer Peptides

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

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Improved solid phase synthesis of C-terminal peptide aldehydes

Cited by 85 publications

References 18 publications

An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV Mpro) Inhibitors

An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV Mpro) Inhibitors

A Novel Class of Intrinsic Proteasome Inhibitory Gene Transfer Peptides

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

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Product

Resources

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An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV M^pro) Inhibitors

An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV M^pro) Inhibitors