FEBS Journal

This special issue on ‘Engineering toxins for 21st century therapies’ provides a critical review of the current state of multifaceted aspects of toxin research by some of the leading researchers in the field. It also highlights the clinical potential and challenges for development of novel biologics based on engineered toxin derived products

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A major unmet clinical need exists for long-acting neurotherapeutics to alleviate chronic pain in patients unresponsive to available non-addictive analgesics. This review describes a recombinant strategy for engineering new generations of botulinum neurotoxin-based therapeutics for attenuating transmitter release from pain-sensing neurons. Combining identified advantageous features from two serotypes yielded a novel, long-lasting and synergistically acting biotherapeutic with antinociceptive potential

Clostridium botulinum neurotoxins are the most potent toxins known. They cause botulism, a deadly disease in humans and animals, and are both public health hazard and potential biowarfare agent. Botulinum neurotoxin consists of multiple domains, each domain being responsible for a specific function in its toxicity. This review describes their molecular structures and discusses the structure-function relation of each domain

There are seven botulinum neurotoxins (BoNTS) serotypes (A-G). BoNT/C and BoNT/D serotypes include mosaic toxins that are organized as D-C and C-D toxins. BoNT/C, BoNT/D, and BoNT/D-SA lack components of the ganglioside binding pocket that exist within other BoNT serotypes, but possess a unique ganglioside binding loop. Defining how BoNTs enter host cells provides insight towards extending BoNT therapys

Cell navigation is the process whereby cells or cytoplasmic extensions are guided from one point to another in multicellular organisms. Here we review the important functions of several v- and t-SNAREs proteins, necessary for membrane fusion, in migration, axon growth and guidance. We conclude that endosomal SNAREs are important for cell navigation, opening avenues for fundamental research and therapeutic applications

The high structural homology of botulinum neurotoxin serotypes paves the way to exchange domains to alter pharmacodynamic characteristics of BoNTs without impairing structural integrity e.g.: the exchange of the H_CC domain exhibiting the ganglioside and protein receptor binding sites in BoNT/A yielded a hybrid neurotoxin with increased receptor binding affinity and potency which leads towards an improved peripheral muscle relaxant

The translocation (T) domain of diphtheria toxin acts as a specialized pH-dependent chaperone for the catalytic (C) domain of the toxin during the initial steps of translocation. T stabilizes the partially folded states of C corresponding to each step of the process. Interestingly, this chaperone activity acts on very different states of C ie: in solution, membrane-bound and membrane inserted

Various bacterial protein toxins and effectors target the actin cytoskeleton. Binary actin-ADP-ribosylating exotoxins cause ADP-ribosylation of actin at Arg177, thereby inhibiting actin polymerization. Photorhabdus luminescens toxin complex that ADP-ribosylates actin at Thr148, promotes actin polymerization and forms actin aggregates. A third group of bacterial toxins/effectors (e.g. Vibrio cholerae RTX toxin) catalyses a chemical cross-linking reaction of actin thereby forming oligomers, while blocking the polymerization of actin to functional filaments

Snake venoms are cocktails of enzymes and non-enzymatic proteins. Here, we describe the structures of the common snake venom enzymes, namely, acetylcholinesterase, L-amino acid oxidase, phospholipase A2, serine proteinase, and metalloproteinase, and their complexes. We discuss the contribution of these structures in understanding the mechanisms of catalysis and inhibition as well as in the structure-based design of new, potent inhibitors

The cytolethal distending toxin, produced by Gram negative bacteria, and colibactin, secreted by commensal and extraintestinal pathogenic Escherichia coli strains, are the first bacterial toxins known to cause DNA damage in eukaryotic cells. We reviewed the cellular responses induced by these toxins, focusing on how prolonged intoxication may lead to chronic inflammation, accumulation of genomic instability, and tumor progression

Clostridium perfringensε-toxin is the etiologic agent of enterotoxaemia and appears to target the brain and kidneys. The crystal structure of ε-toxin reveals similarity to aerolysin from Aeromonas hydrophila, parasporin-2 from Bacillus thuringiensis, and a lectin from Laetiporus sulphurous. Like these toxins, ε-toxin forms pores in target cell membranes, but differs from these toxins because of its high specificity and potency

Clostridium perfringensε-toxin is a potent lethal toxin, which is responsible for animal enterotoxemia. It is structurally related to aerolysin and Clostridium septicumα-toxin. These toxins heptamerize, form pores through the plasma membrane, and induce cell necrosis, ε-toxin being the most potent. ε-toxin accumulates in the kidneys, passes the blood brain barrier and stimulates the glutamate release

Pasteurella multocida toxin (PMT), a member of the dermonecrotic toxin family that includes toxins from Bordetella, Escherichia coli and Yersinia, stimulates host cell mitogenic and survival pathways, while inhibiting pathways involved in cellular differentiation. Structural and biochemical studies demonstrate that PMT modulates these signaling pathways through deamidation of a critical active site glutamine residue in its heterotrimeric G-protein targets

Pasteurella multocida toxin (PMT) binds preferentially to phosphatidylcholine and sphingomyelin developed on TLC plates, incorporated into liposomes, or loaded onto BiaCore L1 chips. Surface plasmon resonance analysis of PMT binding to ghosts from HEK-293T cells treated with phospholipase D, sphingomyelinase, or trypsin suggests interplay among phosphatidylcholine, sphingomyelin and protein coreceptors in the cellular binding of PMT

Superantigens, made by the Gram-positive pathogens Staphylococcus aureus and Streptococcus pyogenes, induce a massive cytokine cascade through their interactions with T cells and antigen presenting cells to cause toxic shock syndrome. In this review we cover the additional ability of superantigens to induce proinflammatory cytokines and chemokines from epithelial cells as a way to initiate disease from mucosal surfaces

Pertussis toxin is a major virulence factor of Bordetella pertussis, the etiological agent of whooping cough, and also one of the main antigens in all current pertussis vaccines. It is one of the most complex bacterial toxins, composed of five different subunits and organized in an A-B structure, in which the A protomer expresses ADPribosyltransferase activity and the B oligomer is responsible for toxin binding to the target cell receptors. After binding the toxin traffics via a retrograde transport to the target substrate. As a fully assembled protein it is secreted through the bacterial cell wall by a type IV secretion system

The modular structure and corresponding mechanism of action of Pseudomonas exotoxin A (PE) are amenable to extensive modifications that can redirect the potent cytotoxicity of this virulence factor toward a therapeutic purpose. This review summarizes our current understanding of PE, its intoxication pathway, and ongoing efforts to convert this toxin into a treatment for cancer