Journal
CHEMMEDCHEM
Volume 17, Issue 11, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202200050
Keywords
PPIase; Pin1; 4; peptide synthesis; molecular modelling; biological activity
Categories
Funding
- European Union's Horizon 2020 (EU) Research and Innovation Programme under the Marie Sklodowska-Curie grant [721906-TRACT]
- MIUR-PRIN [20175SA5JJ]
- Epigenetic Hallmarks of Multiple Sclerosis (acronym Epi-MS) (Merit Ranking Area ERC LS) in VALERE 2019 Program [415]
- VALERE 2020-Progetto competitivo CIRCE in risposta al bando [138]
- Campania Regional Government Technology Platform Lotta alle Patologie Oncologiche: iCURE
- Campania Regional Government FASE2: IDEAL
- Universita degli Studi di Siena within the CRUI-CARE Agreement
- MIUR, Proof of Concept [POC01_00043]
- POR Campania FSE 2014-2020 ASSE III
- PON RICERCA E INNOVAZIONE 2014-2020-DD n. 2893 del 5-11-2018 - Avviso Pubblico Dottorati di Ricerca con Caratterizzazione Industriale [DOT1349104, CUP: B22G19000950006]
- MISE 2020 [1682]
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In this study, a series of peptide-based Pin1 inhibitors were developed and the compound 5 k demonstrated higher binding affinity to Pin1. Comparative analysis of molecular models identified chemical elements that may enhance inhibitory potency, pharmacological properties, and selectivity of future peptide-based Pin1 inhibitors. Furthermore, conjugation of 5 k with R8 resulted in the derivative R8-5 k, which exhibited antiproliferative effects on cancer cell lines.
Pin1 catalyzes the cis-trans isomerization of pThr-Pro or pSer-Pro amide bonds of various proteins involved in several physio/pathological processes. In this framework, recent research activity is directed toward the identification of new selective Pin1 inhibitors. Here, we developed a set of peptide-based Pin1 inhibitors. Direct-binding experiments allowed the identification of the peptide-based inhibitor 5 k (methylacetyl-l-alanyl-l-histidyl-l-prolyl-l-phenylalaninate) as a potent ligand of Pin1. Notably, 5 k binds Pin1 with higher affinity than Pin4. The comparative analysis of molecular models of Pin1 and Pin4 with the selected compound gave a rational explanation of the biochemical activity and pinpointed the chemical elements that, if opportunely modified, may further improve inhibitory potency, pharmacological properties, and selectivity of future peptide-based parvulin inhibitors. Since 5 k showed limited cell penetration and no antiproliferative activity, it was conjugated to a polyarginine stretch (R8), known to promote cell penetration of peptides, to obtain the R8-5 k derivative, which displayed antiproliferative effects on cancer cell lines over non-tumor cells. The effect of R8 on cell proliferation was also investigated. This work warrants caution about applying the R8 strategy in the development of cell-penetrating antiproliferative peptides, as it is not inert.
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