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Metallodrugs Having Improved Pharmacological Properties, and Methods of Manufacture and Use Thereof

a technology of pharmacological properties and improved ligands, applied in the field of pharmacological properties with improved ligands, and methods of manufacture and use thereof, can solve the problem of unnecessary high affinity binding of ligand moiety, and achieve the effect of improving pharmacological properties

Inactive Publication Date: 2014-12-25
METALLOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about improving the treatment of various biochemical targets by combining molecules that can bind to those targets with a metal binding moiety, which can modify proteins and nucleic acids. The resulting molecule, known as a metallodrug or metallotherapeutic, can have better pharmacological properties and can be more effective in treating various targets such as bacteria, viruses, fungus, and cancer cells. The method involves covalently conjugating a therapeutic molecule to the metal binding moiety. Overall, this patent provides a way to enhance the efficacy of existing therapeutic molecules and potentially develop new treatments for various biochemical targets.

Problems solved by technology

In contrast to traditional drug discovery programs, in which candidate drugs display high affinity but reversible binding to a therapeutic target, high affinity binding of a ligand moiety is unnecessary, and even undesirable, according to the catalytic metallodrug concepts described herein.

Method used

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  • Metallodrugs Having Improved Pharmacological Properties, and Methods of Manufacture and Use Thereof
  • Metallodrugs Having Improved Pharmacological Properties, and Methods of Manufacture and Use Thereof
  • Metallodrugs Having Improved Pharmacological Properties, and Methods of Manufacture and Use Thereof

Examples

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example 1

Relationship Between Kinetic / Thermodynamic Data in Controlling Catalytic MetalloDrug Efficiency

[0121]A range of metallopeptide derivatives have been examined with affinities varying from 10 nM (Gly-Gly-His-Asp-D-Glu-Leu-Ile-Cha-Cys-Pro-Cha-Asp-Leu) to 48 μM (Gly-Gly-His-Asp-Glu-Met-Glu-Glu-Cys). A comparison of relative binding affinity versus catalytic efficiency for HCV protease inactivation reveals an inverse correlation between these parameters. This stems from the relationship between affinity and the on / off rate constants for binding (KA=kon / koff), where higher affinity binding is promoted by larger kon and / or smaller koff values. By contrast, efficient catalytic turnover requires koff values that are preferably no smaller than the rate constant for the inactivation chemistry (kcat), to ensure the availability of metallodrug catalyst for new target molecules, and will be best promoted by relatively high values for both kon and koff, which will result in weaker KA values. Those...

example 2

Buforin II Metallodrugs

[0123]Buforin II is a 21-amino acid antimicrobial peptide having antimicrobial activity against a broad spectrum of microbial organisms, including Gram-positive and Gram-negative bacteria, as well as fungi. The buforin peptide adopts an amphipathic helical structure in a hydrophobic environment, and has been shown to penetrate the membrane of target cells and bind to nucleic acids within the cells at micromolar concentrations.

[0124]A copper ATCUN derivative of buforin II (CuGGH-TRSSRAGLQFPVG RVHRLLRK) was synthesized and the activity of the derivative was compared to that of the native buforin II sequence by assessing the sensitivity of various bacterial species as measured by establishing the Minimum Inhibitory Concentration (MIC).

[0125]Relative MIC determinations were established by standard broth dilution methods using nutrient broth and a cell density corresponding to 105 colony forming units in a 200 μL volume. MIC values were determined as the lowest con...

example 3

Lisinopril Metallodrugs Targeting Angiotensin-Converting Enzyme (ACE)

[0126]Lisinopril was purchased from Cayman Chemical Company and stored at −20° C. in powder form, and ESI-TOF-MS analysis confirmed the expected mass of 404 amu. Recombinant human somatic ACE (sACE-1: Leu30-Leu1261, with C-terminal His tag, >95% purity by SDS-PAGE under reducing conditions), originally isolated from an NS0-derived murine myeloma cell line, was purchased from R&D Systems as a stock solution containing 12.5 mM Tris, 75 mM NaCl, 0.5 μM ZnCl2, and 40% (v / v) glycerol, pH 7.5 with [sACE-1]=0.434 mg / mL, and divided into single use aliquots prior to storing at −20° C. Fluorogenic substrate Mca-RPPGFSAFK(Dnp)-OH was purchased from R&D Systems, dissolved in DMSO, divided into single use aliquots, and stored at −20° C. The bifunctional compound NHS-DOTA was purchased from Macrocyclics and stored at −20° C. in powder form. N-hydroxysuccinimide (NHS) was purchased from GenScript, and 1-ethyl-3-[3-dimethyl amino...

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Abstract

It is an object of the present invention to provide improved pharmacological properties to molecules which bind to a target with low affinity (hereinafter referred to as a “ligand moiety”) through linkage of such molecules to a metal binding moiety, thereby generating a combination molecule commonly referred to as a “metallodrug” or “metallotherapeutic.” The metal binding domain of metallodrugs typically catalyzes oxido-reductase chemistry or acts as a Lewis-Acid catalyst, resulting in modification of proteins and nucleic acids that are in close proximity due to binding of the ligand moiety to its target.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 13 / 470,299 filed on May 12, 2012 which claims the benefit of U.S. Provisional Application No. 61 / 485,528 filed May 12, 2011.[0002]The present application is a continuation of U.S. patent application Ser. No. 13 / 470,299 filed on May 12, 2012, which claims priority to U.S. Provisional Patent Application 61 / 485,528 filed on May 12, 2011. The contents of the above applications are hereby incorporated by reference in their entirety, including all tables, figures, sequence listings and claims.STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH AND DEVELOPMENT[0003](Not Applicable)THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT[0004](Not Applicable)REFERENCE TO AN APPENDIX[0005](Not Applicable)BACKGROUND OF THE INVENTION[0006]The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/825C07F17/02C07H21/00A61K38/10C07H23/00A61K38/16A61K31/424
CPCC07K14/825A61K38/16C07F17/02C07H21/00A61K38/10C07H23/00A61K31/424C07K2319/20C07K7/06C07K2319/70A61K38/00C07K5/022A61K47/547A61P31/00
Inventor COWAN, JAMES A.COWAN, ADA S.PALMER, DONNA T.
Owner METALLOPHARM
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