Harnessing the Membrane Translocation Properties of AB Toxins for Therapeutic Applications.

Numa Piot,F Gisou Van Der Goot,Oksana A Sergeeva

doi:10.3390/toxins13010036

Numa Piot, F Gisou Van Der Goot + Show 1 more

Open Access

https://doi.org/10.3390/toxins13010036

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Journal: Toxins	Publication Date: Jan 6, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: École Polytechnique Fédérale de Lausanne

Abstract

Over the last few decades, proteins and peptides have become increasingly more common as FDA-approved drugs, despite their inefficient delivery due to their inability to cross the plasma membrane. In this context, bacterial two-component systems, termed AB toxins, use various protein-based membrane translocation mechanisms to deliver toxins into cells, and these mechanisms could provide new insights into the development of bio-based drug delivery systems. These toxins have great potential as therapies both because of their intrinsic properties as well as the modular characteristics of both subunits, which make them highly amenable to conjugation with various drug classes. This review focuses on the therapeutical approaches involving the internalization mechanisms of three representative AB toxins: botulinum toxin type A, anthrax toxin, and cholera toxin. We showcase several specific examples of the use of these toxins to develop new therapeutic strategies for numerous diseases and explain what makes these toxins promising tools in the development of drugs and drug delivery systems.

Highlights

The FDA is increasingly approving biological drugs
We focus on how the internalization mechanisms of three AB toxins—botulinum toxin type A, anthrax toxin, and cholera toxin—can be used in different therapeutic approaches (Table 1)
In opposition to botulinum toxin type A (BoNT/A), evidence suggest that Lethal factor (LF) has a very short half-life in the cytosol and its long-term effect relies on its ability to remain dormant in intraluminal vesicles (ILVs) which stochastically back-fuse with the membrane of endosomes over a long period of time [21]

Summary

Introduction

The FDA is increasingly approving biological drugs. In 2018, these protein-based drugs made up 25% of FDA approvals and included antibodies, growth factors, hormones, and enzymes that target a broad range of diseases [1]. Botulinum toxin subtypes seem to internalize using the same pathway, they bind to different receptors with variable expression in the different neuronal cell types and their catalytic subunits target different proteins of the SNARE complex, inducing variations in the inhibition of synaptic vesicle fusion. These two aspects of botulinum toxin, aside from its intrinsic therapeutic properties, allow for the development of new therapeutic strategies for numerous diseases. In opposition to BoNT/A, evidence suggest that LF has a very short half-life in the cytosol and its long-term effect relies on its ability to remain dormant in ILVs which stochastically back-fuse with the membrane of endosomes over a long period of time [21]

Anthrax Toxin Therapeutic Applications

Cholera Toxin Therapeutic Applications

Findings

Discussion