Getting Across the Cell Membrane: An Overview for Small Molecules, Peptides, and Proteins

Abstract

The ability to efficiently access cytosolic proteins is desired in both biological research and medicine. However, targeting intracellular proteins is often challenging, because to reach the cytosol, exogenous molecules must first traverse the cell membrane. This review provides a broad overview of how certain molecules are thought to cross this barrier, and what kinds of approaches are being made to enhance the intracellular delivery of those that are impermeable. We first discuss rules that govern the passive permeability of small molecules across the lipid membrane, and mechanisms of membrane transport that have evolved in nature for certain metabolites, peptides, and proteins. Then, we introduce design strategies that have emerged in the development of small molecules and peptides with improved permeability. Finally, intracellular delivery systems that have been engineered for protein payloads are surveyed. Viewpoints from varying disciplines have been brought together to provide a cohesive overview of how the membrane barrier is being overcome.

Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs

“…Various factors could cause a lack of bioactivity including targeting of a nonfunctional site (binding has no downstream effect), inadequate cellular permeability, and compound localization to an undesired compartment. Chemotypes have been identified that improve cellular uptake,(70) including conjugation of polyarginine,(71) as well as those that influence localization. (72) Such data could be incorporated into a traditional medicinal chemistry approach or chemical similarity searching.…”

Engineering Polymersomes for Diagnostics and Therapy

“…[11] Given that many of the drug targets are localized in the subcellular compartments, an efficient translocation of the particles across the cell membrane is essential to attain desired therapeutic outcomes. [12] Endocytosis provides a means of cellular uptake of polymersomes that cannot enter the cells by passive diffusion. [13,14] Polymersomes initiate endocytosis by forming contacts with cell surface receptors.…”

An Investigation into Rigidity–Activity Relationships in BisQAC Amphiphilic Antiseptics

“…C 10 to C 12 ) result in improved selectivities for bacterial membranes hinting at an amphiphilic “sweet spot” that can be further leveraged by structural modifications enabled by organic synthesis. We are also interested in investigating whether some QACs simply permeabilize the membrane as opposed to fully lysing the cell, and if this varies by QAC architecture; such experiments are precedented [22] and represent a future direction for our groups.…”