Short peptide pharmacophores developed from protein phosphatase-1 disrupting peptides (PDPs)

Abstract: PP1 is a major phosphoserine/threonine-specific phosphatase that is involved in diseases such as heart insufficiency and diabetes. PP1-disrupting peptides (PDPs) are selective modulators of PP1 activity that release its catalytic subunit, which then dephosphorylates nearby substrates. Recently, PDPs enabled the creation of phosphatase-recruiting chimeras, which are bifunctional molecules that guide PP1 to a kinase to dephosphorylate and inactivate it. However, PDPs are 23mer peptides, which is not optimal for their use in therapy due to potential stability and immunogenicity issues. Therefore, we present here the sequence optimization of the 23mer PDP to a 5mer peptide, involving several attempts considering structure-based virtual screening, high throughput screening and peptide sequence optimization. We provide here a strong pharmacophore as lead structure to enable PP1 targeting in therapy or its use in phosphatase-recruiting chimeras in the future

Location
Deutsche Nationalbibliothek Frankfurt am Main
Extent
Online-Ressource
Language
Englisch
Notes
Bioorganic & medicinal chemistry. - 65 (2022) , 116785, ISSN: 1464-3391

Event
Veröffentlichung
(where)
Freiburg
(who)
Universität
(when)
2022
Creator
Fontanillo, Miriam
Trębacz, Małgorzata
Reinkemeier, Christopher Dieter
Avilés Huerta, Daniela
Uhrig, Ulrike C.
Sehr, Peter
Köhn, Maja
Contributor
Abteilung Integrative Signalforschung

DOI
10.1016/j.bmc.2022.116785
URN
urn:nbn:de:bsz:25-freidok-2294958
Rights
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Last update
25.03.2025, 1:54 PM CET

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Associated

Time of origin

  • 2022

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