title: Determination of the optimal cell-penetrating peptide sequence for intestinal insulin delivery based on molecular orbital analysis with self-organizing maps.
abstract: Our recent work has shown that the intestinal absorption of insulin can be improved significantly by coadministration of cell-penetrating peptides (CPPs), especially penetratin. However, a relatively high dose of penetratin is required to adequately stimulate the intestinal absorption of insulin. Therefore, in this study, we sought to determine the CPP that most effectively enhanced intestinal insulin absorption. An in situ loop absorption study using 26 penetratin analogues suggested that the chain length, hydrophobicity, and amphipathicity of the CPPs, as well as their basicity, contribute to their absorption-enhancing efficiency. Moreover, a molecular orbital method with self-organizing maps (SOMs) classification suggested that multiple factors, including the molecular weight, basicity, the lowest unoccupied molecular orbital energy, absolute hardness, and chemical potential of CPPs, are associated with their effects on intestinal insulin absorption. Furthermore, the new CPPs proposed by SOM clustering had a marked capacity to interact with insulin, and their ability to enhance insulin absorption was much stronger than that of the original penetratin. Therefore, the peptide sequence that optimally enhances intestinal insulin absorption could be defined by SOM with the molecular orbital method, and our present work emphasizes the utility of such methodologies in the development of effective drug delivery systems.
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Hyogo 650-8586, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Kamei
authors.forename: Shingo
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Mariko
authors.initials: M
authors.lastname: Takeda-Morishita
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Terasawa
authors.forename: Akihito
authors.initials: A
authors.lastname: Yasuda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ida
authors.forename: Reiji
authors.initials: R
authors.lastname: Nishio
authors.forename: Kozo
authors.initials: K
authors.lastname: Takayama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D007328:Insulin; D011994:Recombinant Proteins