Antimicrobial Peptidomimetics with Activity Towards Cancer Cells

Abstract

AMP toxicity and selectivity are poorly understood due to challenges in measuring polydisperse interactions of AMPs within lipid environments. Native or noncovalent mass spectrometry (MS) has recently made significant strides in characterizing the stoichiometry of polydisperse protein complexes and lipid interactions. Here, we employ lipoprotein nanodiscs as a membrane mimetic to assemble AMP complexes for native MS. The nanodiscs are ionized under non-denaturing conditions to introduce the entire nanodisc complex with embedded AMP into the mass spectrometer. By precisely measuring the mass of the intact nanodisc complexes, we can measure the oligomeric state of the AMP without disrupting the lipid bilayer. As a positive control, we observed that gramicidin A forms dimers exclusively, although multiple dimers can be inserted into the nanodisc with sufficient concentration. Ongoing work is investigating AMP complexes with unknown stoichiometries, including LL-37, alamethicin, and melittin. We are also exploring the kinetics of complex assembly by monitoring the formation of specific oligomeric species over time. Ultimately, our goal is that these novel measurements of AMP complex assembly and stoichiometry will shed light on the mechanism of their selectivity and toxicity.

A Novel Strategy for the Design of Aurein 1.2 Analogs with Enhanced Bioactivities by Conjunction of Cell-Penetrating Regions

“…In this study, the peptide demonstrated anti-proliferation activity against 90% of human cancer cell lines tested. However, its anti-proliferation activity was moderate at concentrations of 10 −4 -10 −5 M [21][22][23]. In this study, the aim was to further increase the antimicrobial and anti-proliferation activity of aurein 1.2 to obtain a series of potent, broad-spectrum multifunctional peptides.…”

Cancer-Associated Gangliosides as a Therapeutic Target for Host Defense Peptide Mimics

“…11 Monolayers of DPPC mixed with saturated dipalmitoyl-phosphatidylserine (DPPS) are employed to characterize OAK interactions with anionic phospholipids. 12 Although other lipids are negatively charged, such as dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), DPPS was chosen since it occurs in higher abundance in human cells and has been implicated in other important physiological processes. 13,14 DPPG is often used as a model system for bacterial cell membranes.…”

“…The insertion of octameric OAK, dodecanoyllysyl-hepta­(aminooctanoyllysyl)-amide (C 12 K-7α8) from the aqueous subphase into model lipid membranes is probed using constant-pressure insertion assays and X-ray reflectivity . Monolayers of DPPC mixed with saturated dipalmitoyl-phosphatidylserine (DPPS) are employed to characterize OAK interactions with anionic phospholipids . Although other lipids are negatively charged, such as dipalmitoyl- sn -glycero-3-phosphoglycerol (DPPG), DPPS was chosen since it occurs in higher abundance in human cells and has been implicated in other important physiological processes. , DPPG is often used as a model system for bacterial cell membranes .…”

Synthesis of second-generation self-assembling Gemini Amphiphilic Pseudopeptides

“…In addition, peptide-like molecules are easy to synthesize and they usually show low unspecific toxicity and good biocompatibility. [44][45][46][47][48][49][50][51][52][53][54] However, the fast biodegradation rate of the peptide bond represents the main drawback of these molecules. A possible solution would be the combination of peptide-like moieties with non-peptidic artificial structures, which will implement an increased stability in biological media.…”