Targeting the Inside of Cells with Biologicals: Toxin Routes in a Therapeutic Context

Abstract

Numerous toxins translocate to the cytosol in order to fulfil their function. This demonstrates the existence of routes for proteins from the extracellular space to the cytosol. Understanding these routes is relevant to multiple aspects related to therapeutic applications. These include the development of anti-toxin treatments, the potential use of toxins as shuttles for delivering macromolecular cargo to the cytosol or the use of drugs based on toxins. Compared with other strategies for delivery, such as chemicals as carriers for macromolecular delivery or physical methods like electroporation, toxin routes present paths into the cell that potentially cause less damage and can be specifically targeted. The efficiency of delivery via toxin routes is limited. However, low-delivery efficiencies can be entirely sufficient, if delivered cargoes possess an amplification effect or if very few molecules are sufficient for inducing the desired effects. This is known for example from RNA-based vaccines that have been developed during the coronavirus disease 2019 pandemic as well as for other approved RNA-based drugs, which elicited the desired effect despite their typically low delivery efficiencies. The different mechanisms by which toxins enter cells may have implications for their technological utility. We review the mechanistic principles of the translocation pathway of toxins from the extracellular space to the cytosol, the delivery efficiencies, and therapeutic strategies or applications that exploit toxin routes for intracellular delivery.

Protective Effects of a Jellyfish-Derived Thioredoxin Fused with Cell-Penetrating Peptide TAT-PTD on H2O2-Induced Oxidative Damage

“…Furthermore, toxin routes present paths into the cell that potentially cause less damage to the membrane and can be specifically targeted, contributing greatly to the development of drug delivery in the fields of cancer therapy, antivirals, and protein misfolding diseases. However, this strategy retains some limitations, including the limited selection of molecules that must fulfill multiple criteria and the existing immunity in human populations, which has to be assessed individually [ 43 ].…”

The Clostridium botulinum C2 Toxin Subunit C2IIa Delivers Enzymes with Positively Charged N-Termini into the Cytosol of Target Cells

“…Therefore, molecular transport systems for efficient delivery of therapeutic proteins and peptides are urgently needed to overcome this problem. Bacterial protein toxins should be the ideal candidates, since they are by nature designed to efficiently deliver enzymes, i.e., their A-subunits cross membranes into the cytosol of target cells (for reviews, see [ 55 , 56 ]). One of the best characterized molecules for this purpose is the anthrax toxin pore PA 63 , which has been used to deliver a large variety of cargo molecules into the cytosol of target cells (for review, see [ 27 ]).…”

Towards a Dataset for State of the Art Protein Toxin Classification

“…While screening novel or modified proteins and peptides for potentially dangerous and toxic effects is an important step in verification of therapeutic design, venoms and toxins themselves have been recognized as an incredible source of bioactive peptides, incurring interest as potential bases for treatment options (17)(18)(19). The division between helpful and harmful is subtle and an expanding area of interest that may be enhanced with computational toxin classifiers.…”