Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction

Institut for Lægemiddeldesign og Farmakologi

Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction. / Balboa, Javier R.; Essig, Dominik J.; Ma, Sana; Karer, Nichlas; Clemmensen, Louise S.; Pedersen, Søren W.; Joerger, Andreas C.; Knapp, Stefan; Østergaard, Søren; Strømgaard, Kristian.

I: Journal of Medicinal Chemistry, Bind 66, Nr. 1, 2023, s. 976-990.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Balboa, JR, Essig, DJ, Ma, S, Karer, N, Clemmensen, LS, Pedersen, SW, Joerger, AC, Knapp, S, Østergaard, S & Strømgaard, K 2023, 'Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction', Journal of Medicinal Chemistry, bind 66, nr. 1, s. 976-990. https://doi.org/10.1021/acs.jmedchem.2c01803

APA

Balboa, J. R., Essig, D. J., Ma, S., Karer, N., Clemmensen, L. S., Pedersen, S. W., Joerger, A. C., Knapp, S., Østergaard, S., & Strømgaard, K. (2023). Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction. Journal of Medicinal Chemistry, 66(1), 976-990. https://doi.org/10.1021/acs.jmedchem.2c01803

Vancouver

Balboa JR, Essig DJ, Ma S, Karer N, Clemmensen LS, Pedersen SW o.a. Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction. Journal of Medicinal Chemistry. 2023;66(1):976-990. https://doi.org/10.1021/acs.jmedchem.2c01803

Author

Balboa, Javier R. ; Essig, Dominik J. ; Ma, Sana ; Karer, Nichlas ; Clemmensen, Louise S. ; Pedersen, Søren W. ; Joerger, Andreas C. ; Knapp, Stefan ; Østergaard, Søren ; Strømgaard, Kristian. / Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction. I: Journal of Medicinal Chemistry. 2023 ; Bind 66, Nr. 1. s. 976-990.

Bibtex

@article{01a69e86bab94946b910e6501322c0d2,

title = "Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction",

abstract = "The complex between the N-methyl-d-aspartate receptor (NMDAR), neuronal nitric oxide synthase (nNOS), and the postsynaptic density protein-95 (PSD-95) is an attractive therapeutic target for the treatment of acute ischemic stroke. The complex is formed via the PDZ protein domains of PSD-95, and efforts to disrupt the complex have generally been based on C-terminal peptides derived from the NMDAR. However, nNOS binds PSD-95 through a β-hairpin motif, providing an alternative starting point for developing PSD-95 inhibitors. Here, we designed a cyclic nNOS β-hairpin mimetic peptide and generated cyclic nNOS β-hairpin peptide arrays with natural and unnatural amino acids (AAs), which provided molecular insights into this interaction. We then optimized cyclic peptides and identified a potent inhibitor of the nNOS/PSD-95 interaction, with the highest affinity reported thus far for a peptide macrocycle inhibitor of PDZ domains, which serves as a template for the development of treatment for acute ischemic stroke.",

author = "Balboa, {Javier R.} and Essig, {Dominik J.} and Sana Ma and Nichlas Karer and Clemmensen, {Louise S.} and Pedersen, {S{\o}ren W.} and Joerger, {Andreas C.} and Stefan Knapp and S{\o}ren {\O}stergaard and Kristian Str{\o}mgaard",

year = "2023",

doi = "10.1021/acs.jmedchem.2c01803",

language = "English",

volume = "66",

pages = "976--990",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "1",

}

RIS

TY - JOUR

T1 - Development of a Potent Cyclic Peptide Inhibitor of the nNOS/PSD-95 Interaction

AU - Balboa, Javier R.

AU - Essig, Dominik J.

AU - Ma, Sana

AU - Karer, Nichlas

AU - Clemmensen, Louise S.

AU - Pedersen, Søren W.

AU - Joerger, Andreas C.

AU - Knapp, Stefan

AU - Østergaard, Søren

AU - Strømgaard, Kristian

PY - 2023

Y1 - 2023

N2 - The complex between the N-methyl-d-aspartate receptor (NMDAR), neuronal nitric oxide synthase (nNOS), and the postsynaptic density protein-95 (PSD-95) is an attractive therapeutic target for the treatment of acute ischemic stroke. The complex is formed via the PDZ protein domains of PSD-95, and efforts to disrupt the complex have generally been based on C-terminal peptides derived from the NMDAR. However, nNOS binds PSD-95 through a β-hairpin motif, providing an alternative starting point for developing PSD-95 inhibitors. Here, we designed a cyclic nNOS β-hairpin mimetic peptide and generated cyclic nNOS β-hairpin peptide arrays with natural and unnatural amino acids (AAs), which provided molecular insights into this interaction. We then optimized cyclic peptides and identified a potent inhibitor of the nNOS/PSD-95 interaction, with the highest affinity reported thus far for a peptide macrocycle inhibitor of PDZ domains, which serves as a template for the development of treatment for acute ischemic stroke.

AB - The complex between the N-methyl-d-aspartate receptor (NMDAR), neuronal nitric oxide synthase (nNOS), and the postsynaptic density protein-95 (PSD-95) is an attractive therapeutic target for the treatment of acute ischemic stroke. The complex is formed via the PDZ protein domains of PSD-95, and efforts to disrupt the complex have generally been based on C-terminal peptides derived from the NMDAR. However, nNOS binds PSD-95 through a β-hairpin motif, providing an alternative starting point for developing PSD-95 inhibitors. Here, we designed a cyclic nNOS β-hairpin mimetic peptide and generated cyclic nNOS β-hairpin peptide arrays with natural and unnatural amino acids (AAs), which provided molecular insights into this interaction. We then optimized cyclic peptides and identified a potent inhibitor of the nNOS/PSD-95 interaction, with the highest affinity reported thus far for a peptide macrocycle inhibitor of PDZ domains, which serves as a template for the development of treatment for acute ischemic stroke.

U2 - 10.1021/acs.jmedchem.2c01803

DO - 10.1021/acs.jmedchem.2c01803

M3 - Journal article

C2 - 36580549

AN - SCOPUS:85146192961

VL - 66

SP - 976

EP - 990

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -

ID: 333703115