Lumican Peptides: Rational Design Targeting ALK5/TGFBRI.
Lumican, a small leucine rich proteoglycan (SLRP), is a component of extracellular matrix which also functions as a matrikine regulating multiple cell activities. In the cornea, lumican maintains corneal transparency by regulating collagen fibrillogenesis, promoting corneal epithelial wound healing, regulating gene expression and maintaining corneal homeostasis. We have recently shown that a peptide designed from the 13 C-terminal amino acids of lumican (LumC13) binds to ALK5/TGFBR1 (type1 receptor of TGFβ) to promote wound healing. Herein we evaluate the mechanism by which this synthetic C-terminal amphiphilic peptide (LumC13), binds to ALK5. These studies clearly reveal that LumC13-ALK5 form a stable complex. In order to determine the minimal amino acids required for the formation of a stable lumican/ALK5 complex derivatives of LumC13 were designed and their binding to ALK5 investigated in silico. These LumC13 derivatives were tested both in vitro and in vivo to evaluate their ability to promote corneal epithelial cell migration and corneal wound healing, respectively. These validations add to the therapeutic value of LumC13 (Lumikine) and aid its clinical relevance of promoting the healing of corneal epithelium debridement. Moreover, our data validates the efficacy of our computational approach to design active peptides based on interactions of receptor and chemokine/ligand.
Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, 45267, USA.
Tarsis Ferreira
TF
Gesteira
Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, 45267, USA.
Vivien J
VJ
Coulson-Thomas
Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, 45267, USA.
Yong
Y
Yuan
Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, 45267, USA.
Jianhua
J
Zhang
Departamento de Bioquímica, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
Helena B
HB
Nader
Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, 45267, USA.
Winston W-Y
WW
Kao
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003315:Cornea / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D000071234:Lumican / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014945:Wound Healing / Q000187:drug effects
D000071234:Lumican; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse