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Methods and compositions to inhibit edema factor and adenylyl cyclase

a technology of edema factor and adenylyl cyclase, which is applied in the direction of drug compositions, antibacterial agents, biocides, etc., can solve the problems of suppressing the functions of macrophages, limiting the protection of the body, and toxins are lethal, so as to prevent the loss of intestinal fluid. , to achieve the effect of treating and/or preventing intestinal fluid loss

Inactive Publication Date: 2012-01-12
MISSION PHARMACAL CO INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for treating and preventing intestinal fluid loss in a subject. The method involves administering a therapeutically effective amount of a specific compound to the subject. The compound can have various structures and can be substituted with different functional groups. The patent also provides specific examples of the compounds that can be used for the method. The technical effect of the patent is to provide a reliable and effective treatment for intestinal fluid loss in a subject.

Problems solved by technology

The physiological significance of these bacteria needing to increase cAMP in the respiratory tract is not entirely clear, but it is known that cAMP inhibits phagocytosis of bacteria by macrophages (mφ) and polymorphonuclear neutrophils (PMNs), which would limit the protection of the body against bacteria.
Both toxins are lethal when injected into mice, and they suppress the functions of macrophages, polymorphpneutrophils, and lymphocytes.
High levels of cAMP perturb the water homeostasis of the cell leading to abnormalities in the intracellular signaling pathways and chloride channel stimulation (Ajuha et al., 2004; Ascenzi et al., 2002; Peterson et al.

Method used

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  • Methods and compositions to inhibit edema factor and adenylyl cyclase
  • Methods and compositions to inhibit edema factor and adenylyl cyclase
  • Methods and compositions to inhibit edema factor and adenylyl cyclase

Examples

Experimental program
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example 1

Protein Database Structures Used and Active Site Regions

[0261]1) 1K90 (Drum et al., 2002): the crystal structure of the adenylyl cyclase domain of anthrax edema factor (EF) in complex with both calmodulin and a non-cyclizable nucleotide analogue, 3′-deoxy-ATP (3′dATP) with resolution 2.75 Å and R-Value 0.225. The non-cyclizable 3′dATP lies at the substrate-binding pocket, which is shown in FIGS. 3(A and E). In 1K90, the metal is Yb3+, a crystallization additive, rather than Mg2+, the presumed physiological metal ion. The one Yb3+ coordinates with 2 negatively charged carboxyl groups from residues Asp491 (Yb—O distance: 2.14 Å, 2.56 Å), Asp493 (2.16 Å, 2.23 Å) and His577 (Yb—N, 2.78 Å) and coordinates with a negative charged oxygen atom from the α-phosphate group of 3′-dATP(Yb—O: 2.38 Å). Besides forming coordinate bonds with Yb3+, the most notable phosphate interactions are made by Lys 346 (which contacts oxygen atoms from all three phosphates, the hydrogen bond distance between Lys...

example 2

Docking Programs and Methods

[0267]1) AutoDock (version 3.0.5) (Brisson et al., 2004; Morris et al., 1996): To set search parameters, the Lamarckian Genetic Algorithm (LGA) was used and the number of GA runs was 200 and population size was 100. The active site was defined using AutoGrid. The grid size was set to 90×90×90 points with grid spacing of 0.375 Å. The center of the ligand from the corresponding crystal structure was set to be the grid box center. The ligand and solvent were removed from the crystal structure and the remaining protein model was used in docking procedure. The best ranked conformation is selected from the conformation with the lowest binding energy. For the Zn ion in 1CJV, its parameters are set to radius, 0.87 Å; well depth, 0.35 kcal / mol and charge: +0.95e.

[0268]2) LigandFit / Cerius2(version 4.10) (Venkatachalam et al., 2003): Procedures are as implemented in Cerius2(version 4.10). The poses are evaluated by DockScore. There are two types of DockScore, one is...

example 3

Pharmacophore Design Methods

[0273]Fragment database. The fragment database consisted of 3-D structures (MOL2 files built in SYBYL) of about 60 small molecules, containing hydrogen bond donor / acceptor or hydrophobic moieties, with at most one rotatable bond. These were either common ionizable molecules, or were selected from the SYBYL fragment database.

[0274]HINT score: The Hydropathic INTeractions, or HINT, program (Formabaio et al., 2003; Formabaio et al., 2004; Cozzini et al., 2002) utilizes experimental solvent partitioning data as a basis for an empirical molecular interaction model that calculates free energy scores that were shown to accurately reproduce experimental measurements of binding (Formabaio et al., 2003; Formabaio et al., 2004; Cozzini et al., 2002). “Hydropathic” interactions are non-covalent interactions such as hydrogen-bonding, acid-base, Coulombic, and hydrophobic interactions. The HINT calculation is the summation of hydropathic interactions between all atom p...

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Abstract

Small molecules and their derivatives are described for the treatment and / or prevention of intestinal fluid loss. Also disclosed are methods of using said molecules and their derivatives to treat and / or prevent conditions associated with increased levels of 3′,5′-adenosine monophosphate. Specific compositions of the invention are also novel.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 60 / 944,375 filed on Jun. 15, 2007, and U.S. Provisional Application No. 61 / 035,269 filed on Mar. 10, 2008, both of which are incorporated herein by reference in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The present invention was developed with funds from the United States Government grants number NIAID U01AI5385802 and DAMD 170210699. Therefore, the United States Government has certain rights in the invention.TECHNICAL FIELD[0003]The present invention relates generally to treatment of biological conditions and / or chemical compounds. The present invention also relates to a method of treating conditions caused by increased 3′,5′-adenosine monophosphate levels and compositions used to treat such conditions. Additionally, the invention relates to a method of treating intestinal fluid loss.BACKGROUND OF THE INVENTION[0004]The pathogen...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/438A61K31/196A61P31/04C07C229/60C07C229/52A61K31/24A61K31/122C07D471/04
CPCA61K31/216A61K31/47A61K31/122A61K31/44A61K31/192A61K31/34A61K2300/00A61P1/00A61P1/12A61P15/00A61P29/00A61P31/00A61P31/04A61P35/00Y02A50/30
Inventor SCHEIN, CATHERINE H.GILBERTSON, SCOTT R.PETERSON, JOHNNY W.CHEN, DELIANGESTERLLA-JIMENEZ, MARIAWALTER, MARY A.GAO, JIAN
Owner MISSION PHARMACAL CO INC
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