Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Computational and Systems Biology Graduate Program, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Biophys J. 2022 Jan 18;121(2):277-287. doi: 10.1016/j.bpj.2021.12.018. Epub 2021 Dec 21.
Mucus is a selectively permeable hydrogel that protects wet epithelia from pathogen invasion and poses a barrier to drug delivery. Determining the parameters of a particle that promote or prevent passage through mucus is critical, as it will enable predictions about the mucosal passage of pathogens and inform the design of therapeutics. The effect of particle net charge and size on mucosal transport has been characterized using simple model particles; however, predictions of mucosal passage remain challenging. Here, we utilize rationally designed peptides to examine the integrated contributions of charge, hydrophobicity, and spatial configuration on mucosal transport. We find that net charge does not entirely predict transport. Specifically, for cationic peptides, the inclusion of hydrophobic residues and the position of charged and hydrophobic residues within the peptide impact mucosal transport. We have developed a simple model of mucosal transport that predicts how previously unexplored amino acid sequences achieve slow versus fast passage through mucus. This model may be used as a basis to predict transport behavior of natural peptide-based particles, such as antimicrobial peptides or viruses, and assist in the engineering of synthetic sequences with desired transport properties.
黏液是一种具有选择透过性的水凝胶，能够保护湿润的上皮组织免受病原体入侵，并对药物输送构成障碍。确定促进或阻止粒子通过黏液的参数非常关键，因为这将有助于预测病原体在黏膜上的穿透，并为治疗药物的设计提供信息。已经使用简单的模型粒子对粒子的净电荷和大小对黏膜传输的影响进行了表征；然而，黏膜穿透的预测仍然具有挑战性。在这里，我们利用合理设计的肽来研究电荷、疏水性和空间构象对黏膜传输的综合贡献。我们发现净电荷并不能完全预测传输。具体来说，对于阳离子肽，带电荷和疏水性残基在肽中的位置和疏水性残基的包含会影响黏膜传输。我们已经开发了一种简单的黏膜传输模型，可以预测以前未探索的氨基酸序列如何实现缓慢或快速通过黏液。该模型可用于预测天然基于肽的粒子（如抗菌肽或病毒）的传输行为，并有助于设计具有所需传输特性的合成序列。
