Design and Synthesis of Oligopeptidic Parvulin Inhibitors
| Autor: | Nicola Relitti, A. Prasanth Saraswati, Gabriele Carullo, Alessandro Papa, Alessandra Monti, Rosaria Benedetti, Eugenia Passaro, Simone Brogi, Vincenzo Calderone, Stefania Butini, Sandra Gemma, Lucia Altucci, Giuseppe Campiani, Nunzianna Doti |
|---|---|
| Přispěvatelé: | Relitti, Nicola, Saraswati, A Prasanth, Carullo, Gabriele, Papa, Alessandro, Monti, Alessandra, Benedetti, Rosaria, Passaro, Eugenia, Brogi, Simone, Calderone, Vincenzo, Butini, Stefania, Gemma, Sandra, Altucci, Lucia, Campiani, Giuseppe, Doti, Nunzianna |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Models Molecular Organic Chemistry biological activity Peptidylprolyl Isomerase Biochemistry molecular modelling peptide synthesis Pin1/4 PPIase NIMA-Interacting Peptidylprolyl Isomerase PPIase * Pin1/4 * peptide synthesis * molecular modelling * biological activity Drug Discovery Molecular Medicine General Pharmacology Toxicology and Pharmaceutics Phosphorylation Peptides |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|