Designer Toxins are peptide ligands with custom biological properties that act on a wide variety of ion channels, other cell-surface receptors, and enzymatic pathways ("receptors"). Designer Toxins are produced by a proprietary technology platform which generate thousands to millions of novel combinatorial variants of evolution-tested, target-biased animal toxins and a screening platform to isolate those hits that are active on the pharmaceutical targets of interest in their native cellular milieu or in a purified form. Designer Toxins can be employed to identify new hits or leads for drug development, to optimize known ligands (e.g., selectivity, mechanism of action, pharmacokinetics), and to validate therapeutic target selection. Public domain examples produced by Designer Toxins are high-affinity, selective ligands for Kv1.3 and KcsA K+ channels.
Today, animal venom toxins are the source of a number of major medications, including first-in-class agents, with indications for a diverse range of diseases from cardiovascular disorders to metabolic and to chronic pain. Additionally venom toxins are the source of a number of diagnostic and drug-cosmetic agents.
Designer Toxins (i) generate de novo peptide ligands with custom biological properties, and (ii) are able to modify existing peptides to achieve a desired property, functional or structural. Areas of applicability:
Developed at the University of Chicago by Zoltan Takacs and colleagues, Designer Toxins is a platform that generates variability based on a set of template peptides and identifies those with the desired properties. It is implemented by state-of-the-art combinatorial chemistry and functional genomics, in scalable, high-throughput fashion.
Typically, templates are a select set of animal venom toxins with known pharmacology that are varied to achieve novel properties against pharmaceutical targets. Key features include, the vast number of novel molecules created, evolution-tested molecular motifs, and target-specificity of the library.
Designer Toxin libraries hold from thousands to over a million novel molecules, representing a vast pool of non-random variations - intentionally introduced and defined -, all derived from natural templates.
Designer Toxins are mosaics (chimeras) of natural toxin motifs. Consequently, they exhibit novel and fine-tuned biological properties compared to the natural templates.
The biological function of animal venoms is to immobilize and kill prey or predator in seconds to minutes. Perfected by millions of years of evolution, venom toxins target a plethora of vital receptors key to neuromuscular, cardiovascular, hemostatic, and other life functions. Toxins bind to targets with high affinity and are chemically stable.
Of 150,000 venomous animal species, there is an estimated 20 million toxins.
Designer Toxin libraries are designed and constructed based on natural toxin templates that are known to target a particular receptor class (for example, potassium channels). With preserving key chemical features, the resulting combinatorial elements will retain the inherent bias for the intended receptor class, while, however, the library holds now an unparalleled amount of variability allowing the identification of ligands with fine-tuned, sought-after properties.
Designer Toxin examples (currently in the public domain) that were identified from libraries designed and produced by Zoltan Takacs and colleagues:
>2KIR:A|PDBID|CHAIN|SEQUENCE
INVKCSLPQQCIKPCKDAGMRFGKCMNKKCRCYSPDB ID: 2KIR
Target: K+ channel subtype Kv1.3, validated target for autoimmune diseases
Ki, human Kv1.3: 1.0 nM (in Xenopus oocyte)
Toxin templates: scorpions (order: Scorpiones)
Library diversity: 11,220 elements
Library's target bias: potassium (K+) channels
Clinical significance: K+ channel subtype Kv1.3 is a validated target for autoimmune diseases. (A first-in-class Kv1.3 K+ channel inhibitor, dalazatide by KPI Therapeutics, is in clinical trial.)
Ref: 2009 Proc Natl Acad Sci USA 106, 22211; 2017 Curr Opin Chem Biol 38, 97; US Patent 2009075773.
>2N6B:A|PDBID|CHAIN|SEQUENCE
ACKDYLPKSECTQFRCRTSMKYRLNLCKKTCGTCPDB ID: 2N6B
Target: K+ channel KcsA, the prototype K+ channel
Ki, KcsA-Shaker: 0.5 nM (Xenopus oocyte)
Toxin templates: cnidarians (phylum: Cnidaria)
Library diversity: 1,562,750 elements
Library's target bias: potassium (K+) channels
Clinical significance: This is the largest library of ShK molecular scaffold variants ever produced. An ShK derivative (dalazatide by KPI Therapeutics) is in clinical trial for autoimmune disorders (indication for myositis, cutaneous lupus, psoriasis, psoriatic arthritis).
Ref: 2004 Biosci Rep 24, 75; 2015 Proc Natl Acad Sci USA 112, E7013.
Zoltan Takacs is a molecular pharmacologist and inventor specialized in the functional and genomic aspects of ligand-receptor interactions. He is the co-inventor of Designer Toxins, a technology platform for the high-throughput screening of animal venom toxins in search of novel therapeutic leads. Takacs' Designer Toxin libraries resulted in leads for Kv1.3 K+ channel implicated in autoimmune diseases, and a ligand for KcsA, the first K+ channel whose structure was established by X-ray crystallography yet it lacked a selective inhibitor. Takacs holds a Ph.D. in pharmacology from Columbia University, he completed his postdoctoral research at Rockefeller University and Yale University, and was a faculty at the University of Chicago before launching ToxinTech aimed for the development of novel therapeutic leads from animal venoms. He is a recipient of the Columbia Earth Institute Fellowship and National Geographic Society's Emerging Explorer awards. From academia to biotech, Takacs has lectured widely around the world, and has an established international network for accessing toxin samples. His research has been featured on CNN, BBC, PBS and the National Geographic Channel.
Zoltan Takacs
toxintech.com
zoltan@toxintech.com
