The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach

Joshi, Shilvi; Chen, Lang; Winter, Michael B.; Lin, Yi-Lun; Yang, Yang; Shapovalova, Mariya; Smith, Paige M.; Liu, Chang; Li, Fang; LeBeau, Aaron M.

doi:10.1038/s41598-017-01542-5

The Rational Design of Therapeutic Peptides for Aminopeptidase N using a Substrate-Based Approach

Journal Article · Tue May 02 00:00:00 EDT 2017 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-017-01542-5· OSTI ID:1430325

Joshi, Shilvi ^[1]; ^[1]; Winter, Michael B. ^[2]; Lin, Yi-Lun ^[1]; Yang, Yang ^[1]; Shapovalova, Mariya ^[1]; Smith, Paige M. ^[1]; Liu, Chang ^[1]; Li, Fang ^[1]; LeBeau, Aaron M. ^[1]

Univ. of Minnesota Medical School, Minneapolis, MN (United States)
Univ. of California, San Francisco, CA (United States)

The M1 family of metalloproteases represents a large number of exopeptidases that cleave single amino acid residues from the N-terminus of peptide substrates. One member of this family that has been well studied is aminopeptidase N (APN), a multifunctional protease known to cleave biologically active peptides and aide in coronavirus entry. The proteolytic activity of APN promotes cancer angiogenesis and metastasis making it an important target for cancer therapy. To understand the substrate specificity of APN for the development of targeted inhibitors, we used a global substrate profiling method to determine the P1–P4' amino acid preferences. Here, the key structural features of the APN pharmacophore required for substrate recognition were elucidated by x-ray crystallography. By combining these substrate profiling and structural data, we were able to design a selective peptide inhibitor of APN that was an effective therapeutic both in vitro and in vivo against APN-expressing prostate cancer models.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health

OSTI ID:: 1430325

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 7; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs Węglarz-Tomczak, Ewelina; Talma, Michał; Giurg, Mirosław Oncotarget, Vol. 9, Issue 50 https://doi.org/10.18632/oncotarget.25532	journal	June 2018
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Beyond function: Engineering improved peptides for therapeutic applications Adhikari, Sayanee; Leissa, Jesse A.; Karlsson, Amy J. AIChE Journal, Vol. 66, Issue 3 https://doi.org/10.1002/aic.16776	journal	September 2019
Phosphinic Dehydrodipeptides: Diversification of the P1′ Residue with the Morita–Baylis–Hillman Acetates and Inhibition of Alanyl Aminopeptidases Talma, Michał International Journal of Peptide Research and Therapeutics, Vol. 26, Issue 4 https://doi.org/10.1007/s10989-019-10004-7	journal	January 2020
Quantitative Multiplex Substrate Profiling of Peptidases by Mass Spectrometry Lapek, John D.; Jiang, Zhenze; Wozniak, Jacob M. Molecular & Cellular Proteomics, Vol. 18, Issue 5 https://doi.org/10.1074/mcp.tir118.001099	journal	January 2019
Distinct Epitopes on CD13 Mediate Opposite Consequences for Cell Adhesion Garay-Canales, Claudia A.; Licona-Limón, Ileana; Ortega, Enrique BioMed Research International, Vol. 2018 https://doi.org/10.1155/2018/4093435	journal	January 2018
Molecular Imaging of Aminopeptidase N in Cancer and Angiogenesis Schreiber, Cynthia L.; Smith, Bradley D. Contrast Media & Molecular Imaging, Vol. 2018 https://doi.org/10.1155/2018/5315172	journal	June 2018

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