TY - JOUR
T1 - Discovery and mechanistic characterization of a structurally-unique membrane active peptide
AU - Bansal, Shivani
AU - Su, Wan Chih
AU - Budamagunta, Madhu
AU - Xiao, Wenwu
AU - Ajena, Yousif
AU - Liu, Ruiwu
AU - Voss, John C
AU - Carney, Randy
AU - Parikh, Atul N.
AU - Lam, Kit S.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Membrane active peptides (MAPs) have gained wide interest due to their far reaching applications in drug discovery and drug delivery. The search for new MAPs, however, has been largely skewed with bias selecting for physicochemical parameters believed to be important for membrane activity, such as alpha helicity, cationicity and hydrophobicity. Here we carry out a search-and-find strategy to screen a 100,000-membered one-bead-one-compound (OBOC) combinatorial peptide library for lead compounds, agnostic of those physicochemical constraints. Such a synthetic strategy also permits expansion of our peptide repertoire to include unnatural amino acids. Using this approach, we discovered a structurally unique lead peptide LBF14, a linear 14-mer peptide, that induces gross morphological disruption of membranes, irrespective of membrane composition. Further, we demonstrate that the unique insertion mechanism of the peptide, visualized by spinning disc confocal microscopy and further analyzed by electron paramagnetic resonance measurements, may be the cause of this large scale membrane deformation. We also demonstrate the robustness, reproducibility, and potential application of this technique to discover and characterize new membrane active peptides that display activity by local insertion and subsequent allosteric effects leading to global membrane disruption.
AB - Membrane active peptides (MAPs) have gained wide interest due to their far reaching applications in drug discovery and drug delivery. The search for new MAPs, however, has been largely skewed with bias selecting for physicochemical parameters believed to be important for membrane activity, such as alpha helicity, cationicity and hydrophobicity. Here we carry out a search-and-find strategy to screen a 100,000-membered one-bead-one-compound (OBOC) combinatorial peptide library for lead compounds, agnostic of those physicochemical constraints. Such a synthetic strategy also permits expansion of our peptide repertoire to include unnatural amino acids. Using this approach, we discovered a structurally unique lead peptide LBF14, a linear 14-mer peptide, that induces gross morphological disruption of membranes, irrespective of membrane composition. Further, we demonstrate that the unique insertion mechanism of the peptide, visualized by spinning disc confocal microscopy and further analyzed by electron paramagnetic resonance measurements, may be the cause of this large scale membrane deformation. We also demonstrate the robustness, reproducibility, and potential application of this technique to discover and characterize new membrane active peptides that display activity by local insertion and subsequent allosteric effects leading to global membrane disruption.
KW - Combinatorial library
KW - Giant unilamellar vesicles
KW - Interfacial activity
KW - Membrane active peptide
KW - Membrane activity
KW - Membrane dynamics
UR - http://www.scopus.com/inward/record.url?scp=85087306827&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087306827&partnerID=8YFLogxK
U2 - 10.1016/j.bbamem.2020.183394
DO - 10.1016/j.bbamem.2020.183394
M3 - Article
C2 - 32562695
AN - SCOPUS:85087306827
VL - 1862
JO - Biochimica et Biophysica Acta - Biomembranes
JF - Biochimica et Biophysica Acta - Biomembranes
SN - 0005-2736
IS - 10
M1 - 183394
ER -