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Article: Modification of KL4 Peptide Revealed the Importance of Alpha-Helical Structure for Efficient Small Interfering RNA Delivery

TitleModification of KL4 Peptide Revealed the Importance of Alpha-Helical Structure for Efficient Small Interfering RNA Delivery
Authors
Keywordsalpha helix
beta sheet
cell-penetrating peptide
circular dichroism
peptide modification
Issue Date2020
PublisherMary Ann Liebert, Inc. Publishers. The Journal's web site is located at http://online.liebertpub.com/NAT
Citation
Nucleic Acid Therapeutics, 2020, Epub 2020-04-29 How to Cite?
AbstractA safe and effective delivery system is considered a key to the success of nucleic acid therapeutics. It has been reported that pulmonary surfactants or their components could facilitate the uptake of small interfering RNA (siRNA) into the lung epithelial cells. Previously, our group investigated the use of KL4 peptide, a synthetic cationic peptide that simulates the structural properties of surfactant protein B (SP-B), as siRNA delivery vector. Although KL4 peptide exhibits good in vitro siRNA transfection efficiency on lung epithelial cells, its therapeutic potential is limited by its poor aqueous solubility due to the presence of a high proportion of hydrophobic leucine residues. In this study, we aim to address the solubility issue, designing five different modified peptides by replacing the hydrophobic leucine with alanine or valine, and assess their potential as siRNA delivery vectors. While the modified peptides retain the overall cationic property, their siRNA binding is also affected and their transfection efficiency is inferior to the parent KL4 peptide. A closer examination of the conformation of these peptides by circular dichroism shows that substitution of leucine residues leads to the change of the secondary structure from α-helical content to either β-sheet or more disordered, β-turn conformations. Relatively conservative amino acid substitutions, in terms of hydrophobicity bulk, lead to substantial conformational alteration, heavily impacting siRNA binding and release, cellular uptake, and transfection efficiency. Although the peptide modification strategy employed in this study was unsuccessful in developing an improved version of KL4 peptide for siRNA delivery, it highlights the importance of the α-helical conformation for efficient siRNA transfection, providing useful insights for future development of peptide-based RNA delivery system. Figures
Persistent Identifierhttp://hdl.handle.net/10722/284686
ISSN
2020 Impact Factor: 5.486
2015 SCImago Journal Rankings: 1.651
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorQIU, Y-
dc.contributor.authorLo, JCK-
dc.contributor.authorKwok, KCW-
dc.contributor.authorMason, AJ-
dc.contributor.authorLam, JKW-
dc.date.accessioned2020-08-07T09:01:14Z-
dc.date.available2020-08-07T09:01:14Z-
dc.date.issued2020-
dc.identifier.citationNucleic Acid Therapeutics, 2020, Epub 2020-04-29-
dc.identifier.issn2159-3337-
dc.identifier.urihttp://hdl.handle.net/10722/284686-
dc.description.abstractA safe and effective delivery system is considered a key to the success of nucleic acid therapeutics. It has been reported that pulmonary surfactants or their components could facilitate the uptake of small interfering RNA (siRNA) into the lung epithelial cells. Previously, our group investigated the use of KL4 peptide, a synthetic cationic peptide that simulates the structural properties of surfactant protein B (SP-B), as siRNA delivery vector. Although KL4 peptide exhibits good in vitro siRNA transfection efficiency on lung epithelial cells, its therapeutic potential is limited by its poor aqueous solubility due to the presence of a high proportion of hydrophobic leucine residues. In this study, we aim to address the solubility issue, designing five different modified peptides by replacing the hydrophobic leucine with alanine or valine, and assess their potential as siRNA delivery vectors. While the modified peptides retain the overall cationic property, their siRNA binding is also affected and their transfection efficiency is inferior to the parent KL4 peptide. A closer examination of the conformation of these peptides by circular dichroism shows that substitution of leucine residues leads to the change of the secondary structure from α-helical content to either β-sheet or more disordered, β-turn conformations. Relatively conservative amino acid substitutions, in terms of hydrophobicity bulk, lead to substantial conformational alteration, heavily impacting siRNA binding and release, cellular uptake, and transfection efficiency. Although the peptide modification strategy employed in this study was unsuccessful in developing an improved version of KL4 peptide for siRNA delivery, it highlights the importance of the α-helical conformation for efficient siRNA transfection, providing useful insights for future development of peptide-based RNA delivery system. Figures-
dc.languageeng-
dc.publisherMary Ann Liebert, Inc. Publishers. The Journal's web site is located at http://online.liebertpub.com/NAT-
dc.relation.ispartofNucleic Acid Therapeutics-
dc.rightsNucleic Acid Therapeutics. Copyright © Mary Ann Liebert, Inc. Publishers.-
dc.rightsFinal publication is available from Mary Ann Liebert, Inc., publishers http://dx.doi.org/[insert DOI]-
dc.subjectalpha helix-
dc.subjectbeta sheet-
dc.subjectcell-penetrating peptide-
dc.subjectcircular dichroism-
dc.subjectpeptide modification-
dc.titleModification of KL4 Peptide Revealed the Importance of Alpha-Helical Structure for Efficient Small Interfering RNA Delivery-
dc.typeArticle-
dc.identifier.emailLo, JCK: jasonlck@hku.hk-
dc.identifier.emailLam, JKW: jkwlam@hku.hk-
dc.identifier.authorityLam, JKW=rp01346-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1089/nat.2020.0855-
dc.identifier.hkuros312463-
dc.identifier.volumeEpub 2020-04-29-
dc.identifier.isiWOS:000530001600001-
dc.publisher.placeUnited States-
dc.identifier.issnl2159-3337-

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