Advanced Situation with Recombinant Toxins: Diversity, Production and Application Purposes

Today, the production and use of various samples of recombinant protein/polypeptide toxins is known and is actively developing. This review presents state-of-the-art in research and development of such toxins and their mechanisms of action and useful properties that have allowed them to be implemented into practice to treat various medical conditions (including oncology and chronic inflammation applications) and diseases, as well as to identify novel compounds and to detoxify them by diverse approaches (including enzyme antidotes). Special attention is given to the problems and possibilities of the toxicity control of the obtained recombinant proteins. The recombinant prions are discussed in the frame of their possible detoxification by enzymes. The review discusses the feasibility of obtaining recombinant variants of toxins in the form of protein molecules modified with fluorescent proteins, affine sequences and genetic mutations, allowing us to investigate the mechanisms of toxins’ bindings to their natural receptors.

[1]  J. Bart Classen COVID-19 and Illegal US Bioweapons Activity, an Insider's Revelations , 2022, Trends in Internal Medicine.

[2]  E. Vázquez,et al.  The Diphtheria Toxin Translocation Domain Impairs Receptor Selectivity in Cancer Cell-Targeted Protein Nanoparticles , 2022, Pharmaceutics.

[3]  V. Núñez,et al.  Heterologous Expression and Immunogenic Potential of the Most Abundant Phospholipase A2 from Coral Snake Micrurus dumerilii to Develop Antivenoms , 2022, Toxins.

[4]  Yuliya V. Korolkova,et al.  Optimized method for the recombinant production of a sea anemone’s peptide , 2022, Mendeleev Communications.

[5]  G. Jackson,et al.  Essential Components of Synthetic Infectious Prion Formation De Novo , 2022, Biomolecules.

[6]  U. Subhashini,et al.  A Hybrid Genetic Particle Swarm Optimization Algorithm Based Fusion Protein Functionality Prediction , 2022, Journal of Pharmaceutical Negative Results.

[7]  V. Timofeev,et al.  New formulation of a recombinant anthrax vaccine stabilised with structurally modified plant viruses , 2022, Frontiers in Microbiology.

[8]  J. Kowalska,et al.  Yeasts as a Potential Biological Agent in Plant Disease Protection and Yield Improvement—A Short Review , 2022, Agriculture.

[9]  Jiyan Ma,et al.  Recombinant Mammalian Prions: The “Correctly” Misfolded Prion Protein Conformers , 2022, Viruses.

[10]  Y. Andreev,et al.  Analysis of Structural Determinants of Peptide MS 9a-1 Essential for Potentiating of TRPA1 Channel , 2022, Marine drugs.

[11]  I. Kaltashov,et al.  Genetically detoxified tetanus toxin as a vaccine and conjugate carrier protein , 2022, Vaccine.

[12]  N. Nifantiev,et al.  Cross reacting material (CRM197) as a carrier protein for carbohydrate conjugate vaccines targeted at bacterial and fungal pathogens. , 2022, International journal of biological macromolecules.

[13]  M. Zourob,et al.  Exploring the Utility of ssDNA Aptamers Directed against Snake Venom Toxins as New Therapeutics for Snakebite Envenoming , 2022, Toxins.

[14]  S. Ainsworth,et al.  Exploring the Utility of Recombinant Snake Venom Serine Protease Toxins as Immunogens for Generating Experimental Snakebite Antivenoms , 2022, Toxins.

[15]  F. Conceição,et al.  Clostridium haemolyticum, a review of beta toxin and insights into the antigen design for vaccine development. , 2022, Molecular immunology.

[16]  Kumud Pant,et al.  Emerging trends in immunotoxin targeting cancer stem cells. , 2022, Toxicology in vitro : an international journal published in association with BIBRA.

[17]  M. Zourob,et al.  Exploring the utility of ssDNA aptamers directed against snake venom toxins as new therapeutics for tropical snakebite envenoming , 2022, bioRxiv.

[18]  Naorem Leimarembi Devi,et al.  ToxinPred2: an improved method for predicting toxicity of proteins , 2022, Briefings Bioinform..

[19]  M. Imamura,et al.  Spontaneous generation of distinct prion variants with recombinant prion protein from a baculovirus-insect cell expression system. , 2022, Biochemical and biophysical research communications.

[20]  B. Melnik,et al.  The zinc ions stabilize the three-dimensional structure and are required for the binding of staphylococcal enterotoxin-like protein P (SEIP) with MHC-II receptors. , 2022, Protein expression and purification.

[21]  O. Karpova,et al.  Designing Stable Bacillus anthracis Antigens with a View to Recombinant Anthrax Vaccine Development , 2022, Pharmaceutics.

[22]  V. Tsetlin,et al.  Antiviral Effects of Animal Toxins: Is There a Way to Drugs? , 2022, International journal of molecular sciences.

[23]  M. Fauler,et al.  The Pore-Forming Subunit C2IIa of the Binary Clostridium botulinum C2 Toxin Reduces the Chemotactic Translocation of Human Polymorphonuclear Leukocytes , 2022, Frontiers in Pharmacology.

[24]  G. Püschel,et al.  Discrimination of the Activity of Low-Affinity Wild-Type and High-Affinity Mutant Recombinant BoNT/B by a SIMA Cell-Based Reporter Release Assay. , 2022, Toxins.

[25]  B. Melnik,et al.  The C-terminal domain of Bacillus cereus hemolysin II oligomerizes by itself in the presence of cell membranes to form ion channels. , 2022, International journal of biological macromolecules.

[26]  F. Conceição,et al.  Recombinant Vaccine Design Against Clostridium spp. Toxins Using Immunoinformatics Tools. , 2021, Methods in molecular biology.

[27]  H. Ayat,et al.  Recombinantly expressed MeICT, a new toxin from Mesobuthus eupeus scorpion, inhibits glioma cell proliferation and downregulates Annexin A2 and FOXM1 genes , 2021, Biotechnology Letters.

[28]  Mitchell Ho,et al.  Generation of Single-Domain Antibody-Based Recombinant Immunotoxins. , 2022, Methods in molecular biology.

[29]  L. Possani,et al.  Heterologous expression of four recombinant toxins from Panamanian scorpions of the genus Tityus and Centruroides for production of antivenom , 2021, Toxicon: X.

[30]  V. Gushchin,et al.  A Strategy for the Rapid Development of a Safe Vibrio cholerae Candidate Vaccine Strain , 2021, International journal of molecular sciences.

[31]  S. Conti,et al.  Wickerhamomyces Yeast Killer Toxins’ Medical Applications , 2021, Toxins.

[32]  P. Wolf Targeted Toxins for the Treatment of Prostate Cancer , 2021, Biomedicines.

[33]  Tong Wu,et al.  Recent development and optimization of pseudomonas aeruginosa exotoxin immunotoxins in cancer therapeutic applications. , 2021, International immunopharmacology.

[34]  S. Deyev,et al.  Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology , 2021, International journal of molecular sciences.

[35]  A. Zahmatkesh,et al.  Vaccination against pathogenic clostridia in animals: a review , 2021, Tropical Animal Health and Production.

[36]  G. Cordero-Bueso,et al.  Culturable Yeasts as Biofertilizers and Biopesticides for a Sustainable Agriculture: A Comprehensive Review , 2021, Plants.

[37]  Michael R Hamblin,et al.  Streptococcal bacterial components in cancer therapy , 2021, Cancer Gene Therapy.

[38]  C. Specht,et al.  Vaccines for human fungal diseases: close but still a long way to go , 2021, NPJ vaccines.

[39]  M. Dong,et al.  Shiga Toxins: An Update on Host Factors and Biomedical Applications , 2021, Toxins.

[40]  S. Zara,et al.  Evaluation of Recombinant Kpkt Cytotoxicity on HaCaT Cells: Further Steps towards the Biotechnological Exploitation Yeast Killer Toxins , 2021, Foods.

[41]  Samuel S. Hunter,et al.  The Species-Specific Acquisition and Diversification of a K1-like Family of Killer Toxins in Budding Yeasts of the Saccharomycotina , 2021, PLoS genetics.

[42]  R. Rappuoli,et al.  The role of vaccines in combatting antimicrobial resistance , 2021, Nature Reviews Microbiology.

[43]  Y. Utkin,et al.  α-Conotoxins and α-Cobratoxin Promote, while Lipoxygenase and Cyclooxygenase Inhibitors Suppress the Proliferation of Glioma C6 Cells , 2021, Marine drugs.

[44]  T. Andreeva,et al.  Novel Three-Finger Neurotoxins from Naja melanoleuca Cobra Venom Interact with GABAA and Nicotinic Acetylcholine Receptors , 2021, Toxins.

[45]  F. Conceição,et al.  Evaluation of the expression and immunogenicity of four versions of recombinant Clostridium perfringens beta toxin designed by bioinformatics tools. , 2021, Anaerobe.

[46]  K. Mineev,et al.  New Insectotoxin from Tibellus Oblongus Spider Venom Presents Novel Adaptation of ICK Fold , 2021, Toxins.

[47]  M. El-Sibai,et al.  Recombinant anthrax lethal toxin inhibits cell motility and invasion in breast cancer cells through the dysregulation of Rho GTPases. , 2020, Oncology letters.

[48]  T. Wood,et al.  Type VII Toxin/Antitoxin Classification System for Antitoxins that Enzymatically Neutralize Toxins. , 2020, Trends in microbiology.

[49]  B. Melnik,et al.  A Monoclonal Antibody against the C-Terminal Domain of Bacillus cereus Hemolysin II Inhibits HlyII Cytolytic Activity , 2020, Toxins.

[50]  S. Ermakova,et al.  Sea Anemone Heteractis crispa Actinoporin Demonstrates In Vitro Anticancer Activities and Prevents HT-29 Colorectal Cancer Cell Migration , 2020, Molecules.

[51]  A. Arseniev,et al.  N-Terminal Tagging with GFP Enhances Selectivity of Agitoxin 2 to Kv1.3-Channel Binding Site , 2020, Toxins.

[52]  T. Wood,et al.  Novel polyadenylylation-dependent neutralization mechanism of the HEPN/MNT toxin/antitoxin system , 2020, Nucleic acids research.

[53]  A. Konevega,et al.  Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape , 2020, Cancers.

[54]  S. Zara,et al.  Production of a lyophilized ready-to-use yeast killer toxin with possible applications in the wine and food industries. , 2020, International journal of food microbiology.

[55]  J. Collinge,et al.  Highly infectious prions are not directly neurotoxic , 2020, Proceedings of the National Academy of Sciences.

[56]  V. Babenko,et al.  Novel Bradykinin-Potentiating Peptides and Three-Finger Toxins from Viper Venom: Combined NGS Venom Gland Transcriptomics and Quantitative Venom Proteomics of the Azemiops feae Viper , 2020, Biomedicines.

[57]  J. Tytgat,et al.  Tuning Scorpion Toxin Selectivity: Switching From KV1.1 to KV1.3 , 2020, Frontiers in Pharmacology.

[58]  J. Atabekov,et al.  Two approaches for the stabilization of Bacillus anthracis recombinant protective antigen , 2020, Human vaccines & immunotherapeutics.

[59]  A. Mankin,et al.  Mechanism of translation inhibition by type II GNAT toxin AtaT2 , 2020, Nucleic acids research.

[60]  Meitian Wang,et al.  Characterization of a toxin-antitoxin system in Mycobacterium tuberculosis suggests neutralization by phosphorylation as the antitoxicity mechanism , 2020, Communications Biology.

[61]  A. Sorokan,et al.  Recombinant Bacillus subtilis 26DCryChS line with gene Btcry1Ia encoding Cry1Ia toxin from Bacillus thuringiensis promotes integrated wheat defense against pathogen Stagonospora nodorum Berk. and greenbug Schizaphis graminum Rond. , 2020 .

[62]  Y. Mukaila,et al.  An Appraisal of Antidotes’ Effectiveness: Evidence of the Use of Phyto-Antidotes and Biotechnological Advancements , 2020, Molecules.

[63]  A. Omer,et al.  Comprehensive insights into microbial keratinases and their implication in various biotechnological and industrial sectors: A review. , 2020, International journal of biological macromolecules.

[64]  Anton E Shikov,et al.  No More Tears: Mining Sequencing Data for Novel Bt Cry Toxins with CryProcessor , 2020, Toxins.

[65]  G. Rhie,et al.  Evaluation of the protective efficacy of recombinant protective antigen vaccine (GC1109)-immunized human sera using passive immunization in a mouse model. , 2020, Vaccine.

[66]  M. E. Lanio,et al.  Pore-forming toxins from sea anemones: from protein-membrane interaction to its implications for developing biomedical applications , 2020 .

[67]  M. Geron Production and Purification of Recombinant Toxins. , 2020, Methods in molecular biology.

[68]  B. Andryukov,et al.  Toxin-Antitoxin Systems And Their Role In Maintaining The Pathogenic Potential Of Causative Agents Of Sapronoses. , 2020, Infectious disorders drug targets.

[69]  A. Dashbolaghi,et al.  Cytotoxic and apoptotic properties of a novel nano‐toxin formulation based on biologically synthesized silver nanoparticle loaded with recombinant truncated pseudomonas exotoxin A , 2020, Journal of cellular physiology.

[70]  M. Volteau,et al.  Safety and pharmacodynamics of a novel recombinant botulinum toxin E (rBoNT-E): Results of a phase 1 study in healthy male subjects compared with abobotulinumtoxinA (Dysport®) , 2019, Journal of the Neurological Sciences.

[71]  E. Pardon,et al.  Structural evidence for the critical role of the prion protein hydrophobic region in forming an infectious prion , 2019, PLoS pathogens.

[72]  N. Matoba,et al.  Repeated Oral Administration of a KDEL-Tagged Recombinant Cholera Toxin B Subunit Effectively Mitigates DSS Colitis despite a Robust Immunogenic Response , 2019, Toxins.

[73]  Daisuke Kihara,et al.  NNTox: Gene Ontology-Based Protein Toxicity Prediction Using Neural Network , 2019, Scientific Reports.

[74]  F. Shafiee,et al.  Targeted Diphtheria Toxin-Based Therapy: A Review Article , 2019, Front. Microbiol..

[75]  P. Tarighi,et al.  Preparation of Diphtheria and Pseudomonas Exotoxin A Immunotoxins and Evaluation of Their Cytotoxicity Effect on SK-BR-3, BT-474, and MDA-MB-231 Breast Cancer Cell Lines , 2019, Cancer investigation.

[76]  E. Marcellin,et al.  Vaccine Production to Protect Animals Against Pathogenic Clostridia , 2019, Toxins.

[77]  Y. Cordeiro,et al.  RNA modulates aggregation of the recombinant mammalian prion protein by direct interaction , 2019, Scientific Reports.

[78]  J. Atabekov,et al.  Vaccines against anthrax based on recombinant protective antigen: problems and solutions , 2019, Expert review of vaccines.

[79]  Jing Wang,et al.  Immunotoxins: Targeted Toxin Delivery for Cancer Therapy , 2019, Pharmaceutical Fronts.

[80]  A. N. Noskov,et al.  Camelid VHHs Fused to Human Fc Fragments Provide Long Term Protection Against Botulinum Neurotoxin A in Mice , 2019, Toxins.

[81]  E. Rogozhin,et al.  Expression of spider toxin in entomopathogenic fungus Lecanicillium muscarium and selection of the strain showing efficient secretion of the recombinant protein. , 2019, FEMS microbiology letters.

[82]  S. Jung,et al.  Construction of an immunotoxin via site-specific conjugation of anti-Her2 IgG and engineered Pseudomonas exotoxin A , 2019, Journal of Biological Engineering.

[83]  S. Zara,et al.  Yeast killer toxins: from ecological significance to application. , 2019, Critical reviews in biotechnology.

[84]  Yaroslava M Chalenko,et al.  Hepatoprotective Activity of InlB321/15, the HGFR Ligand of Bacterial Origin, in CCI4-Induced Acute Liver Injury Mice , 2019, Biomedicines.

[85]  B. Berger,et al.  Single dose of DPX-rPA, an enhanced-delivery anthrax vaccine formulation, protects against a lethal Bacillusanthracis spore inhalation challenge , 2019, npj Vaccines.

[86]  K. Chandy,et al.  Antibodies and venom peptides: new modalities for ion channels , 2019, Nature Reviews Drug Discovery.

[87]  W. Bishai,et al.  Second-generation IL-2 receptor-targeted diphtheria fusion toxin exhibits antitumor activity and synergy with anti–PD-1 in melanoma , 2019, Proceedings of the National Academy of Sciences.

[88]  A. Moura-da-Silva,et al.  Design and Production of a Recombinant Hybrid Toxin to Raise Protective Antibodies against Loxosceles Spider Venom , 2019, Toxins.

[89]  V. Uversky,et al.  Binding of LcrV protein from Yersinia pestis to human T-cells induces apoptosis, which is completely blocked by specific antibodies. , 2019, International journal of biological macromolecules.

[90]  V. Ntziachristos,et al.  Neurobiology and therapeutic applications of neurotoxins targeting transmitter release. , 2019, Pharmacology & therapeutics.

[91]  S. Yamasaki,et al.  Development of a bivalent food poisoning vaccine: augmented antigenicity of the C-terminus of Clostridium perfringens enterotoxin by fusion with the B subunit of Escherichia coli Shiga toxin 2 , 2018, International immunology.

[92]  Daisuke Kihara,et al.  Phylo‐PFP: improved automated protein function prediction using phylogenetic distance of distantly related sequences , 2018, Bioinform..

[93]  Soyoun Hwang,et al.  Preparation of lyophilized recombinant prion protein for TSE diagnosis by RT-QuIC , 2018, BMC Research Notes.

[94]  H. Schätzl,et al.  Recombinant prion protein vaccination of transgenic elk PrP mice and reindeer overcomes self-tolerance and protects mice against chronic wasting disease , 2018, The Journal of Biological Chemistry.

[95]  F. Conceição,et al.  Immunogenicity of Clostridium perfringens epsilon toxin recombinant bacterin in rabbit and ruminants. , 2018, Vaccine.

[96]  J. Tytgat,et al.  KV1.2 channel-specific blocker from Mesobuthus eupeus scorpion venom: Structural basis of selectivity , 2018, Neuropharmacology.

[97]  S. Komisarenko,et al.  Particular Features of Diphtheria Toxin Internalization by Resistant and Sensitive Mammalian Cells , 2018, Cytology and Genetics.

[98]  A. Doxey,et al.  Discovery of novel bacterial toxins by genomics and computational biology , 2018, Toxicon : official journal of the International Society on Toxinology.

[99]  M. Isaeva,et al.  Multigene Family of Pore-Forming Toxins from Sea Anemone Heteractis crispa , 2018, Marine drugs.

[100]  J. Rohrer,et al.  Intracellular drug delivery: Potential usefulness of engineered Shiga toxin subunit B for targeted cancer therapy. , 2018, Biotechnology advances.

[101]  E. Grishin,et al.  Pilot production of the recombinant peptide toxin of Heteractis crispa as a potential analgesic by intein-mediated technology. , 2018, Protein expression and purification.

[102]  E. Grishin,et al.  Biotechnological Method for Production of Recombinant Peptide Analgesic (Purotoxin-1) from Geolycosa sp. Spider Poison , 2018, Russian Journal of Bioorganic Chemistry.

[103]  T. Andreeva,et al.  The First Recombinant Viper Three-Finger Toxins: Inhibition of Muscle and Neuronal Nicotinic Acetylcholine Receptors , 2018, Doklady Biochemistry and Biophysics.

[104]  Kumardeep Chaudhary,et al.  In Silico Approach for Prediction of Antifungal Peptides , 2018, Front. Microbiol..

[105]  A. V. Lobanov,et al.  Azemiopsin, a Selective Peptide Antagonist of Muscle Nicotinic Acetylcholine Receptor: Preclinical Evaluation as a Local Muscle Relaxant , 2018, Toxins.

[106]  V. Bachanova,et al.  Development of a Deimmunized Bispecific Immunotoxin dDT2219 against B-Cell Malignancies , 2018, Toxins.

[107]  M. D. Di Bari,et al.  Cofactors influence the biological properties of infectious recombinant prions , 2018, Acta Neuropathologica.

[108]  M. Schmitt,et al.  Production of fluorescent and cytotoxic K28 killer toxin variants through high cell density fermentation of recombinant Pichia pastoris , 2017, Microbial Cell Factories.

[109]  F. Breinig,et al.  Expression of K1 Toxin Derivatives in Saccharomyces cerevisiae Mimics Treatment with Exogenous Toxin and Provides a Useful Tool for Elucidating K1 Mechanisms of Action and Immunity , 2017, Toxins.

[110]  S. Denk,et al.  Rho-inhibiting C2IN-C3 fusion toxin inhibits chemotactic recruitment of human monocytes ex vivo and in mice in vivo , 2017, Archives of Toxicology.

[111]  Fei Wang,et al.  In Situ Capture of Bacterial Toxins for Antivirulence Vaccination , 2017, Advanced materials.

[112]  Daria D. Kharlampieva,et al.  Interaction of Bacteroides fragilis Toxin with Outer Membrane Vesicles Reveals New Mechanism of Its Secretion and Delivery , 2017, Front. Cell. Infect. Microbiol..

[113]  Daisuke Kihara,et al.  Using PFP and ESG Protein Function Prediction Web Servers. , 2017, Methods in molecular biology.

[114]  I. Ahel,et al.  The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA , 2016, Molecular cell.

[115]  M. Mayzel,et al.  An oxygen-sensitive toxin–antitoxin system , 2016, Nature Communications.

[116]  David J. Barlow,et al.  Machine learning can differentiate venom toxins from other proteins having non-toxic physiological functions , 2016, PeerJ Comput. Sci..

[117]  Daisuke Kihara,et al.  The PFP and ESG protein function prediction methods in 2014: effect of database updates and ensemble approaches , 2015, GigaScience.

[118]  Daisuke Kihara,et al.  PFP/ESG: automated protein function prediction servers enhanced with Gene Ontology visualization tool , 2015, Bioinform..

[119]  Juancarlos Chan,et al.  Gene Ontology Consortium: going forward , 2014, Nucleic Acids Res..

[120]  Y. Ghasemi,et al.  Nattokinase: production and application , 2014, Applied Microbiology and Biotechnology.

[121]  Ming Sun,et al.  Mining New Crystal Protein Genes from Bacillus thuringiensis on the Basis of Mixed Plasmid-Enriched Genome Sequencing and a Computational Pipeline , 2012, Applied and Environmental Microbiology.

[122]  James P. Bennett,et al.  Degradation of the Disease-Associated Prion Protein by a Serine Protease from Lichens , 2011, PloS one.

[123]  K. Vercauteren,et al.  Enzymatic digestion of chronic wasting disease prions bound to soil. , 2010, Environmental science & technology.

[124]  K. Vercauteren,et al.  Feasibility of infectious prion digestion using mild conditions and commercial subtilisin. , 2009, Journal of virological methods.

[125]  Michal Linial,et al.  ClanTox: a classifier of short animal toxins , 2009, Nucleic Acids Res..