Potent and Selective Peptidyl Boronic Acid Inhibitors of the Serine Protease Prostate-Specific Antigen

Aaron M. LeBeau; Pratap Singh; John T. Isaacs; Samuel R. Denmeade

doi:10.1016/j.chembiol.2008.05.020

Potent and Selective Peptidyl Boronic Acid Inhibitors of the Serine Protease Prostate-Specific Antigen

Aaron M. LeBeau, Pratap Singh, John T. Isaacs, Samuel R. Denmeade

School of Medicine

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

Prostate cancer cells produce high (microgram to milligram/milliliter) levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the extracellular fluid surrounding prostate cancers but is found at 1,000- to 10,000-fold lower concentrations in the circulation, where it is inactivated due to binding to abundant serum protease inhibitors. The exclusive presence of high levels of active PSA within prostate cancer sites makes PSA an attractive candidate for targeted imaging and therapeutics. A synthetic approach based on a peptide substrate identified first peptide aldehyde and then boronic acid inhibitors of PSA. The best of these had the sequence Cbz-Ser-Ser-Lys-Leu-(boro)Leu, with a K_i for PSA of 65 nM. The inhibitor had a 60-fold higher K_i for chymotrypsin. A validated model of PSA's catalytic site confirmed the critical interactions between the inhibitor and residues within the PSA enzyme.

Original language	English (US)
Pages (from-to)	665-674
Number of pages	10
Journal	Chemistry and Biology
Volume	15
Issue number	7
DOIs	https://doi.org/10.1016/j.chembiol.2008.05.020
State	Published - Jul 21 2008

Keywords

CHEMBIO
PROTEINS

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2008.05.020

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title = "Potent and Selective Peptidyl Boronic Acid Inhibitors of the Serine Protease Prostate-Specific Antigen",

abstract = "Prostate cancer cells produce high (microgram to milligram/milliliter) levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the extracellular fluid surrounding prostate cancers but is found at 1,000- to 10,000-fold lower concentrations in the circulation, where it is inactivated due to binding to abundant serum protease inhibitors. The exclusive presence of high levels of active PSA within prostate cancer sites makes PSA an attractive candidate for targeted imaging and therapeutics. A synthetic approach based on a peptide substrate identified first peptide aldehyde and then boronic acid inhibitors of PSA. The best of these had the sequence Cbz-Ser-Ser-Lys-Leu-(boro)Leu, with a Ki for PSA of 65 nM. The inhibitor had a 60-fold higher Ki for chymotrypsin. A validated model of PSA's catalytic site confirmed the critical interactions between the inhibitor and residues within the PSA enzyme.",

keywords = "CHEMBIO, PROTEINS",

author = "LeBeau, {Aaron M.} and Pratap Singh and Isaacs, {John T.} and Denmeade, {Samuel R.}",

note = "Funding Information: We greatly appreciate the advice on chemical syntheses provided by Aneta Modzelewska and Surojit Sir at Johns Hopkins. This work was supported by an award from the One-in Six Foundation, Akron, Ohio. ",

year = "2008",

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doi = "10.1016/j.chembiol.2008.05.020",

language = "English (US)",

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AU - LeBeau, Aaron M.

AU - Singh, Pratap

AU - Isaacs, John T.

AU - Denmeade, Samuel R.

N1 - Funding Information: We greatly appreciate the advice on chemical syntheses provided by Aneta Modzelewska and Surojit Sir at Johns Hopkins. This work was supported by an award from the One-in Six Foundation, Akron, Ohio.

PY - 2008/7/21

Y1 - 2008/7/21

N2 - Prostate cancer cells produce high (microgram to milligram/milliliter) levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the extracellular fluid surrounding prostate cancers but is found at 1,000- to 10,000-fold lower concentrations in the circulation, where it is inactivated due to binding to abundant serum protease inhibitors. The exclusive presence of high levels of active PSA within prostate cancer sites makes PSA an attractive candidate for targeted imaging and therapeutics. A synthetic approach based on a peptide substrate identified first peptide aldehyde and then boronic acid inhibitors of PSA. The best of these had the sequence Cbz-Ser-Ser-Lys-Leu-(boro)Leu, with a Ki for PSA of 65 nM. The inhibitor had a 60-fold higher Ki for chymotrypsin. A validated model of PSA's catalytic site confirmed the critical interactions between the inhibitor and residues within the PSA enzyme.

AB - Prostate cancer cells produce high (microgram to milligram/milliliter) levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the extracellular fluid surrounding prostate cancers but is found at 1,000- to 10,000-fold lower concentrations in the circulation, where it is inactivated due to binding to abundant serum protease inhibitors. The exclusive presence of high levels of active PSA within prostate cancer sites makes PSA an attractive candidate for targeted imaging and therapeutics. A synthetic approach based on a peptide substrate identified first peptide aldehyde and then boronic acid inhibitors of PSA. The best of these had the sequence Cbz-Ser-Ser-Lys-Leu-(boro)Leu, with a Ki for PSA of 65 nM. The inhibitor had a 60-fold higher Ki for chymotrypsin. A validated model of PSA's catalytic site confirmed the critical interactions between the inhibitor and residues within the PSA enzyme.

KW - CHEMBIO

KW - PROTEINS

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ER -

Potent and Selective Peptidyl Boronic Acid Inhibitors of the Serine Protease Prostate-Specific Antigen

Abstract

Keywords

ASJC Scopus subject areas

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