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Protein synthesis modulators

a technology of ribosomes and modulators, applied in the field of ribosome modulators, can solve the problems of cancerous cells, particularly problematic resistance to anti-infective agents, and the evolution of strains of cells or organisms resistant to currently effective therapeutic agents, and achieve the effect of modulating ribosomal activity and ribosomal activity

Inactive Publication Date: 2014-02-20
MELINTA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The evolution of strains of cells or organisms resistant to currently effective therapeutic agents is an ongoing medical problem.
For example, the development of cancerous cells resistant to certain anti-proliferative agents, such as chemotherapeutic drugs, has long been recognized as a problem in the oncology field.
The problem of resistance to anti-infective agents is particularly problematic for antibiotic therapy.

Method used

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Examples

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example 1

Three-Dimensional Structure of a RNA Microhelix when Associated with the Large Ribosomal Subunit

[0181]Ribosomes were purified and crystallized as described previously (U.S. Patent Application Publication No. US 2002 / 0086308 A1). Crystals containing H. marismortui large ribosomal subunits complexed with the RNA microhelix of Formula I, were obtained by soaking pre-formed, large-subunit crystals in stabilizing buffers containing the RNA microhelix of Formula I.

[0182]The RNA microhelix was solubilized in standard stabilization buffer (Ban et al. (2000) Science 289: 905-920) to a final concentration of about 4.0 mM, and then incubated at 4° C. for 18 hours prior to cryo-vitrification of crystals in liquid propane. X-ray diffraction data were collected at Beamline 14-4 at the European Radiation Synchrotron Facility in Grenoble, France. Data were reduced using denzo or HKL2000 software and scaled with scalepack (Otwinowski (1997) “Processing of X-ray Diffraction Data Collected In Oscillat...

example 2

Three-Dimensional Structure of a RNA Microhelix when Associated with the Large Ribosomal Subunit

[0184]Ribosomes were purified and crystallized as described previously (U.S. Patent Application Publication No. US 2002 / 0086308 A1). Crystals containing H. marismortui large ribosomal subunits complexed with the RNA microhelix of Formula II, were obtained by soaking pre-formed, large-subunit crystals in stabilizing buffers containing the RNA microhelix of Formula II.

[0185]The RNA microhelix was solubilized in standard stabilization buffer (Ban et al. (2000) supra) to a final concentration of about 5.0 mM, and then incubated at 4° C. for 18 hours prior to cryo-vitrification of crystals in liquid propane. X-ray diffraction data were collected at Beamline X25 at Brookhaven National Laboratory in Upton, N.Y. Data were reduced using denzo or HKL2000 software and scaled with scalepack (Otwinowski (1997) “Processing of X-ray Diffraction Data Collected In Oscillation Mode,”Methods in Enzymology 2...

example 3

Additional Three-Dimensional Structures of RNA Microhelices when Associated with the Large Ribosomal Subunit

[0187]Using the general procedures of Example 1, crystals containing H. marismortui large ribosomal subunits complexed with other RNA microhelices (for example, a 5′ ACCA 3′ RNA microhelix) are obtained. The three-dimensional structures of these crystal complexes can be obtained as described in Examples 1 and 2. The resulting structures can also be used to design other candidate molecules useful as protein synthesis modulators.

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Abstract

The invention provides a high resolution three-dimensional structure of a deacylated transfer RNA protein synthesis modulator in association with a large ribosomal subunit. The protein synthesis modulator binds at least a portion of the E-site of a large ribosomal subunit. The invention provides methods for designing and / or identifying analogs of candidate molecules, for example, analogs or derivatives of the protein synthesis modulator, that bind and / or modulate the protein biosynthetic activity of the ribosome.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 12 / 074,200, filed Feb. 29, 2008, which is a continuation of U.S. patent application Ser. No. 10 / 889,378, filed Jul. 12, 2004, and claims the benefit of the filing date of U.S. Provisional Patent Application No. 60 / 490,460, filed Jul. 28, 2003 and U.S. Provisional Patent Application No. 60 / 487,371, filed Jul. 14, 2003, the entire disclosures of each of which are incorporated by reference herein.FIELD OF THE INVENTION[0002]The present invention relates to the field of ribosome modulators, for example, inhibitors of protein biosynthesis, and to methods of making and using such modulators. More particularly, the invention relates to the three-dimensional structures of deacylated transfer RNA-based protein synthesis modulators, either alone or when associated with a large ribosomal subunit, the modulator's binding site within a large ribosomal subunit, and to methods of making and using prote...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G06F19/12G06F19/16G16B5/00G16B15/10
CPCG06F19/16G06F19/12G16C20/50G16B15/00G16B15/10G16B5/00
Inventor WIMBERLY, BRIAN THOMAS
Owner MELINTA THERAPEUTICS
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