PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis
PEPITEM is an immune-modulatory peptide that effectively regulates inflammation and mitigates immune-mediated inflammatory diseases (IMIDs). Here, we identify two independently active tripeptide pharmacophores within PEPITEM and engineered peptidomimetics with enhanced pharmacodynamic properties. Th...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000490 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1825199433471492096 |
|---|---|
| author | Anella Saviano Bonita Apta Samantha Tull Laleh Pezhman Areeba Fatima Mustafa Sevim Antonio Mete Myriam Chimen Anna Schettino Noemi Marigliano Helen M. McGettrick Asif J. Iqbal Francesco Maione G. Ed Rainger |
| author_facet | Anella Saviano Bonita Apta Samantha Tull Laleh Pezhman Areeba Fatima Mustafa Sevim Antonio Mete Myriam Chimen Anna Schettino Noemi Marigliano Helen M. McGettrick Asif J. Iqbal Francesco Maione G. Ed Rainger |
| author_sort | Anella Saviano |
| collection | DOAJ |
| description | PEPITEM is an immune-modulatory peptide that effectively regulates inflammation and mitigates immune-mediated inflammatory diseases (IMIDs). Here, we identify two independently active tripeptide pharmacophores within PEPITEM and engineered peptidomimetics with enhanced pharmacodynamic properties. These peptidomimetics regulate T-cell trafficking in vitro and reduce T-cell, neutrophil and macrophage numbers in the inflamed peritoneal cavity in vivo. In a plaque psoriasis model, topical administration reduced disease severity, inflammation and immune cell infiltration, while regulating cytokine release in macrophages and fibroblasts, as well as keratinocyte proliferation. Th1 and Th17 cell abundance, along with their cytokines, was reduced in secondary lymphoid organs. This expanded functional repertoire of PEPITEM and its derivatives provides innovative tools for countering immune and stromal cell-induced pathology in IMIDs. Moreover, by identifying significantly smaller tripeptide pharmacophores of 14 amino acid PEPITEM, we may be able to deliver substantial financial advantages in synthesis and formulation. The order of magnitude increase in efficacy observed for some peptidomimetics may deliver agents with enhanced pharmacological characteristics compared to the parent PEPITEM sequence. Taken together with other reports on the efficacy of PEPITEM, this study paves the way for the development and translation of a novel class of anti-inflammatory agents which may have utility in a broad range of autoimmune and chronic inflammatory diseases. |
| format | Article |
| id | doaj-art-8f83045b404749f1826093fd9fa799de |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-8f83045b404749f1826093fd9fa799de2025-02-08T04:59:54ZengElsevierPharmacological Research1096-11862025-03-01213107624PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasisAnella Saviano0Bonita Apta1Samantha Tull2Laleh Pezhman3Areeba Fatima4Mustafa Sevim5Antonio Mete6Myriam Chimen7Anna Schettino8Noemi Marigliano9Helen M. McGettrick10Asif J. Iqbal11Francesco Maione12G. Ed Rainger13ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, Naples 80131, ItalyDepartment of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UKDepartment of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UKDepartment of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UKDepartment of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UKDepartment of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UKMedsyndesign Ltd, Advanced Technology Innovation Centre, 5 Oakwood Drive, Loughborough LE11 3QF, UKDepartment of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UKImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, Naples 80131, ItalyImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, Naples 80131, ItalyDepartment of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UKDepartment of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UKImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, Naples 80131, Italy; Correspondence to: Head of ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, Naples 80131, Italy.Department of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK; Correspondence to: Department of Cardiovascular Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK.PEPITEM is an immune-modulatory peptide that effectively regulates inflammation and mitigates immune-mediated inflammatory diseases (IMIDs). Here, we identify two independently active tripeptide pharmacophores within PEPITEM and engineered peptidomimetics with enhanced pharmacodynamic properties. These peptidomimetics regulate T-cell trafficking in vitro and reduce T-cell, neutrophil and macrophage numbers in the inflamed peritoneal cavity in vivo. In a plaque psoriasis model, topical administration reduced disease severity, inflammation and immune cell infiltration, while regulating cytokine release in macrophages and fibroblasts, as well as keratinocyte proliferation. Th1 and Th17 cell abundance, along with their cytokines, was reduced in secondary lymphoid organs. This expanded functional repertoire of PEPITEM and its derivatives provides innovative tools for countering immune and stromal cell-induced pathology in IMIDs. Moreover, by identifying significantly smaller tripeptide pharmacophores of 14 amino acid PEPITEM, we may be able to deliver substantial financial advantages in synthesis and formulation. The order of magnitude increase in efficacy observed for some peptidomimetics may deliver agents with enhanced pharmacological characteristics compared to the parent PEPITEM sequence. Taken together with other reports on the efficacy of PEPITEM, this study paves the way for the development and translation of a novel class of anti-inflammatory agents which may have utility in a broad range of autoimmune and chronic inflammatory diseases.http://www.sciencedirect.com/science/article/pii/S1043661825000490InflammationDiseaseTherapeuticsPeptidesPeptidomimeticsPsoriasis |
| spellingShingle | Anella Saviano Bonita Apta Samantha Tull Laleh Pezhman Areeba Fatima Mustafa Sevim Antonio Mete Myriam Chimen Anna Schettino Noemi Marigliano Helen M. McGettrick Asif J. Iqbal Francesco Maione G. Ed Rainger PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis Pharmacological Research Inflammation Disease Therapeutics Peptides Peptidomimetics Psoriasis |
| title | PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis |
| title_full | PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis |
| title_fullStr | PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis |
| title_full_unstemmed | PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis |
| title_short | PEPITEM, its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis |
| title_sort | pepitem its tripeptide pharmacophores and their peptidomimetic analogues regulate the inflammatory response through parenteral and topical dosing in models of peritonitis and psoriasis |
| topic | Inflammation Disease Therapeutics Peptides Peptidomimetics Psoriasis |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000490 |
| work_keys_str_mv | AT anellasaviano pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT bonitaapta pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT samanthatull pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT lalehpezhman pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT areebafatima pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT mustafasevim pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT antoniomete pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT myriamchimen pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT annaschettino pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT noemimarigliano pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT helenmmcgettrick pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT asifjiqbal pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT francescomaione pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis AT gedrainger pepitemitstripeptidepharmacophoresandtheirpeptidomimeticanaloguesregulatetheinflammatoryresponsethroughparenteralandtopicaldosinginmodelsofperitonitisandpsoriasis |