Botulinum neurotoxin-specific capture agents, compositions, and methods of using and making

A technology of botulinum neurotoxin and capture agent, applied in the direction of isotope introduction into organic compounds, organic chemistry methods, chemical instruments and methods, etc., can solve the problem that molecular inhibitors cannot enter

Active Publication Date: 2018-01-23
CALIFORNIA INST OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Rapid sequestration of BoNT toxins into motor neurons limits current antibody-based therapeutics, yet molecular inhibitors cannot access closed active sites of circulating BoNTs

Method used

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  • Botulinum neurotoxin-specific capture agents, compositions, and methods of using and making
  • Botulinum neurotoxin-specific capture agents, compositions, and methods of using and making
  • Botulinum neurotoxin-specific capture agents, compositions, and methods of using and making

Examples

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Embodiment 1

[0228] Example 1. Screening strategy for botulinum neurotoxin-specific ligands.

[0229] A macrocyclic peptide ligand (Inh-1, Figure 6 and 7 ). Inh-1 with a binding affinity of about 70 nM (k D ) and similar inhibition constants bind to the active site. Using a fully synthetic in situ click epitope targeting approach (e.g. figure 1 shown), used to identify a second peptide macrocycle (L2, Figure 8 and 9 ). L2 exhibits a k of about 80nM D , but no inhibitory effect. Finally, in situ click screening facilitated by BoNT LC was employed to identify linear peptides linking two macrocycles (e.g. figure 2shown). The final bivalent ligand (Inh-2, Figure 10 ) inhibits BoNT LC with an IC50 of 165±15 pM. Inh-2 is also carried into neuronal cells by BoNT itself and inhibits holotoxin in living cells. This technology offers a potentially general approach for the development of peripheral and active-site binders from initial libraries for combinatorial use through in sit...

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Abstract

The application provides stable peptide-based Botulinum neurotoxin (BoNT) serotype A capture agents and methods of use as detection and diagnosis agents and in the treatment of diseases and disorders.The application further provides methods of manufacturing BoNT serotype A capture agents using iterative on-bead in situ click chemistry.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 62 / 133,891, filed March 16, 2015, which is hereby incorporated by reference in its entirety. Background technique [0003] Botulinum neurotoxin (BoNT) type A is the deadliest known toxin. BoNT is produced by some species of the bacterial genus (Clostridium) and is a chemical denervating zinc-dependent protease that blocks neuronal neurogenesis by cleaving one of the three SNARE proteins required for synaptic vesicle formation and release. Ca in muscle junctions 2+ Induced release of acetylcholine. BoNT / A intoxication proceeds through selective binding to neuronal receptors, entry into cells via receptor-mediated endocytosis, escape from endosomes via pH-induced translocation, and finally cleavage of its SNAP-25 base in the cytoplasm thing. BoNT / A consists of a receptor-binding heavy chain and a disulfide-linked catalytic light chain (LC)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/083C07K7/06C07K7/08C07K7/52A61K38/00A61K38/06A61K38/08A61K38/12C07B59/00G01N33/531G06F19/12G16B5/00
CPCG01N33/531G01N2333/33A61K38/005A61K38/12A61K38/06A61K38/08G16B5/00Y02A50/30A61K47/64C07B59/008C07K7/52C07K5/0808C07K7/06C07K2319/01C07B2200/05C07K2319/70A61K38/00A61K47/60C07K7/08
Inventor 布莱克·法罗詹姆斯·R·希斯希瑟·道恩·阿格纽
Owner CALIFORNIA INST OF TECH
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