Mechanism of amphipathic and cargo-delivery peptides

描述(申请人提供)：这项研究的长期目标是开发合理的方法来设计和改进穿膜两亲性多肽，这些多肽是抗生素或细胞溶解的，或者可以携带其他药物分子作为货物进入细胞。实现这一目标的关键知识是确定这些多肽的膜穿透机制。已知这类多肽具有相当大的靶向性，这似乎源于多肽与靶细胞膜脂双层的相互作用，而不需要蛋白质受体的干预。此外，细菌产生抗药性的难度要大得多，因为这需要细菌膜的巨大变化。 与这些多肽的机制相关的三个基本假设将被检验。预测是，多肽序列的特定特征是多肽穿透细胞或破坏细胞膜所必需的。四种自然产生的多肽被选为新序列的基础，这些新序列将用于检验假说。如果正确，一个强大的预测程序将可用于设计具有所需机制的多肽。因此，目的是设计多肽，用于将货物运送到细胞内或用于细胞溶解功能。载物肽可以用来将药物输送到真核细胞中，或者将抗生素输送到细菌细胞中。克服细胞屏障，包括细胞内的隔间，是使用抗生素的主要困难。此外，随着细菌对常规抗生素产生越来越多的耐药性，了解合理设计不容易产生耐药性的新抗生素所需的物理性质是至关重要的。

DESCRIPTION (provided by applicant): The long-term objective of this research is the development of rational methods for the design and improvement of membrane-penetrating, amphipathic peptides that are antibiotic or cytolytic, or can carry other drug molecules as cargo into cells. Critical knowledge in reaching this objective is the determination of the mechanism of membrane penetration by these peptides. Peptides in this class are known to exhibit considerable target specificity, which appears to derive from the interaction of the peptides with the lipid bilayer of the target cell membrane without the intervention of protein receptors. Furthermore, the development of resistance by bacteria is much more difficult because it entails massive changes in the bacterial membranes. Three fundamental hypotheses relating to the mechanism of these peptides will be tested. The prediction is that specific features of the peptide sequences are necessary for peptides to penetrate cells or disrupt the membrane. Four naturally-occurring peptides were selected as the basis for new sequences that will be used to test the hypotheses. If correct, a powerful predictive program will be available to design peptides that function with a desired mechanism. Thus, the aim is to design peptides for cargo-delivery into cells or for cytolytic functions. Cargo-carrying peptides can be used to transport drugs into eukaryotic cells or antibiotics into bacterial cells. Surmounting cellular barriers, including intracellular compartments, is a major difficulty in the use of antibiotics. Furthermore, as bacteria increasingly develop resistance against conventional antibiotics, understanding the physical properties necessary for the rational design of new antibiotics that are not prone to resistance development is of the utmost importance.