Backbone amide linker (BAL) strategy forNα-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis of peptide aldehydes

Kappel, Joseph C.; Bárány, George

doi:10.1002/psc.614

Cited by 21 publications

(23 citation statements)

References 76 publications

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“…Synthesis of Fmoc-amino acid aldehydes 4: Fmoc-amino alcohol (5.36 mmol) obtained from Fmoc-amino acid as described in the literature [39] was dissolved in dry DCM (200 mL). Dess-Martin periodinane (12 mmol, 2.2 equiv) was added and dissolved almost completely followed by water addition (200 mL, 11.1 mmol).…”

Section: Synthetic Proceduresmentioning

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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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: Synthetic Proceduresmentioning

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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“…In order to further refine this sequence and identify PSA inhibitors with lower K i values, we pursued a similar approach and constructed mini-libraries in which the P2 and P3 positions of this inhibitor were systematically modified. As before, a backbone-amide-linker (BAL) approach to create peptide aldehydes on solid phase resin was employed (21). The P2 position amino acid preference was investigated for several reasons: first, we wanted to find a residue that would increase the solubility of the compound in buffer and second, we were interested in trying to incorporate novel unnatural amino acids that would help us to further define the PSA pharmacophore and increase the specificity of the inhibitor for PSA.…”

Section: Resultsmentioning

confidence: 99%

Optimization of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer

LeBeau

Banerjee

Pomper

et al. 2009

Bioorganic & Medicinal Chemistry

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Prostate-Specific Antigen (PSA) is a serine protease biomarker that may play a role in prostate cancer development and progression. The inhibition of PSA’s enzymatic activity with small molecule inhibitors is an attractive and, as of yet, unexploited target. Previously, we reported a series of peptidyl aldehyde and boronic acid based inhibitors of PSA. In this study, the structural requirements in the P2 and P3 positions of peptide based PSA inhibitors are explored through the substitution of a series of natural and unnatural amino acids in these positions. This analysis demonstrated a preference for hydrophobic residues in the P2 position and amino acids with the potential to hydrogen bond in the P3 position. Using this information, a peptide boronic acid inhibitor with the sequence Cbz-Ser-Ser-Gln-Nle-(boro)-Leu was identified with a Ki for PSA of 25 nM. The attachment of a bulky metal chelating group to the amino terminal of this peptide did not adversely affect PSA inhibition. This result suggests that a platform of PSA-inhibitor chelates could be developed as SPECT or PET-based imaging agents for prostate cancer.

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“…All peptide aldehydes inhibitors were synthesized by the method described by Kappel and Barany26 using the backbone amide linker approach. Once protected, aldehydes were attached to the resin and standard Fmoc solid phase peptide synthesis conditions were used for peptide chain elongation on an APTECH Apex 396 40 well peptide synthesizer.…”

Section: Methodsmentioning

confidence: 99%

Molecular insights into substrate specificity of prostate specific antigen through structural modeling

et al. 2009

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Prostate Specific Antigen’s (PSA) role as a biomarker for prostate cancer is well established but the physiological role of its serine protease activity in the pathobiology of normal prostate and prostate carcinogenesis remains largely unknown. In light of recent studies that implicate PSA’s enzymatic activity in the initiation and/or progression of prostate cancer, we performed a molecular modeling study of substrate binding at the catalytic site of PSA wherein a PSA-selective substrate (HSSKLQ) was docked in an acyl-enzyme conformation to a 3-dimensional homology model of PSA. Additionally, virtual positional scanning studies were conducted in order to gain mechanistic insights into substrate recognition of PSA. Subsequently, 13 novel peptide substrates of 6-aa length and 4 peptide substrates with varying length were synthesized and assayed for PSA hydrolysis to evaluate the experimental validity of docking insights,. Additionally, six novel aldehyde-containing transition state analog inhibitors were synthesized and tested for their inhibitory potencies. The experimental data on the hydrolysis rates of the newly synthesized substrates and inhibitory potencies of the aldehyde peptides agreed with the docking predictions, providing validation of the docking methodology and demonstrating its utility towards the design of substrate-mimetic inhibitors that can be used to explore PSA’s role in the pathobiology of prostate cancer.

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Backbone amide linker (BAL) strategy forNα-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis of peptide aldehydes

Cited by 21 publications

References 76 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

Optimization of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer

Molecular insights into substrate specificity of prostate specific antigen through structural modeling

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Backbone amide linker (BAL) strategy forNα-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis of peptide aldehydes

Cited by 21 publications

References 76 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

Optimization of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer

Molecular insights into substrate specificity of prostate specific antigen through structural modeling

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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