Cyclic mimetics of kinase-inhibitory region of Suppressors of Cytokine Signaling 1 : Progress toward novel anti-inflammatory therapeutics
Copyright © 2021 Elsevier Masson SAS. All rights reserved..
Herein we investigated the structural and cellular effects ensuing from the cyclization of a potent inhibitor of JAK2 as mimetic of SOCS1 protein, named PS5. The introduction of un-natural residues and a lactam internal bridge, within SOCS1-KIR motif, produced candidates that showed high affinity toward JAK2 catalytic domain. By combining CD, NMR and computational studies, we obtained valuable models of the interactions of two peptidomimetics of SOCS1 to deepen their functional behaviors. Notably, when assayed for their biological cell responses mimicking SOCS1 activity, the internal cyclic PS5 analogues demonstrated able to inhibit JAK-mediated tyrosine phosphorylation of STAT1 and to reduce cytokine-induced proinflammatory gene expression, oxidative stress generation and cell migration. The present study well inserts in the field of low-molecular-weight proteomimetics with improved longtime cellular effects and adds a new piece to the puzzled way for the conversion of bioactive peptides into drugs.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:221 |
|---|---|
| Enthalten in: |
European journal of medicinal chemistry - 221(2021) vom: 05. Okt., Seite 113547 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
La Manna, Sara [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 06.08.2021 Date Revised 06.08.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.ejmech.2021.113547 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM325730571 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM325730571 | ||
| 003 | DE-627 | ||
| 005 | 20231225193047.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ejmech.2021.113547 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1085.xml |
| 035 | |a (DE-627)NLM325730571 | ||
| 035 | |a (NLM)34023736 | ||
| 035 | |a (PII)S0223-5234(21)00396-2 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a La Manna, Sara |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Cyclic mimetics of kinase-inhibitory region of Suppressors of Cytokine Signaling 1 |b Progress toward novel anti-inflammatory therapeutics |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 06.08.2021 | ||
| 500 | |a Date Revised 06.08.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a Herein we investigated the structural and cellular effects ensuing from the cyclization of a potent inhibitor of JAK2 as mimetic of SOCS1 protein, named PS5. The introduction of un-natural residues and a lactam internal bridge, within SOCS1-KIR motif, produced candidates that showed high affinity toward JAK2 catalytic domain. By combining CD, NMR and computational studies, we obtained valuable models of the interactions of two peptidomimetics of SOCS1 to deepen their functional behaviors. Notably, when assayed for their biological cell responses mimicking SOCS1 activity, the internal cyclic PS5 analogues demonstrated able to inhibit JAK-mediated tyrosine phosphorylation of STAT1 and to reduce cytokine-induced proinflammatory gene expression, oxidative stress generation and cell migration. The present study well inserts in the field of low-molecular-weight proteomimetics with improved longtime cellular effects and adds a new piece to the puzzled way for the conversion of bioactive peptides into drugs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cytokine signaling | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a JAK/STAT | |
| 650 | 4 | |a Mimetic peptides | |
| 650 | 4 | |a Oxidative stress | |
| 650 | 4 | |a SOCS1 | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 650 | 7 | |a Peptidomimetics |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Socs1 protein, mouse |2 NLM | |
| 650 | 7 | |a Suppressor of Cytokine Signaling 1 Protein |2 NLM | |
| 700 | 1 | |a Lopez-Sanz, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Bernal, Susana |e verfasserin |4 aut | |
| 700 | 1 | |a Fortuna, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Mercurio, Flavia A |e verfasserin |4 aut | |
| 700 | 1 | |a Leone, Marilisa |e verfasserin |4 aut | |
| 700 | 1 | |a Gomez-Guerrero, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Marasco, Daniela |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t European journal of medicinal chemistry |d 1994 |g 221(2021) vom: 05. Okt., Seite 113547 |w (DE-627)NLM106608835 |x 1768-3254 |7 nnns |
| 773 | 1 | 8 | |g volume:221 |g year:2021 |g day:05 |g month:10 |g pages:113547 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.ejmech.2021.113547 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 221 |j 2021 |b 05 |c 10 |h 113547 | ||