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Mutagenic nucleoside analogs and uses thereof

a technology of nucleoside analogs and nucleosides, applied in the field of mutagenic nucleoside analogs, can solve the problems of severe reduction of the efficacy of those drugs, and achieve the effects of reducing or avoiding symptoms, signs or causes of the condition, and reducing or minimizing one or more symptoms

Inactive Publication Date: 2017-11-02
MASSACHUSETTS INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes certain compounds that can be used as therapeutic or prophylactic agents in the treatment of viral infections and cancer. These compounds have specific structures and can be transformed into active forms in the body. The transformation can occur through solvolysis or under physiological conditions. The active forms can have various structures and offer advantages such as solubility and tissue compatibility. The compounds described in the patent text can be used alone or in combination with other therapies to provide therapeutic benefits or prevent the condition.

Problems solved by technology

A major obstacle for viral disease treatment is viral persistence, which makes many current anti-rival therapies only temporality effective.
However, drug resistance generated by HIV mutations severely reduces the efficacy of those drugs.

Method used

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  • Mutagenic nucleoside analogs and uses thereof
  • Mutagenic nucleoside analogs and uses thereof
  • Mutagenic nucleoside analogs and uses thereof

Examples

Experimental program
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Effect test

example 1

IR Spectroscopy Tests of KP1212 in Aqueous Solutions

[0258]Methods. For both 1D FTIR and 2D IR experiments, the H / D exchanged KP1212 was dissolved at a concentration of 20 mg / ml (88 mM) in 0.5 M phosphate buffer pD (pH reading in D2O) 7.9. About 25 μl of sample solution was sandwiched between two CaF2 windows separated by a 50 μm TEFLON spacer. Variable-temperature FTIR spectra were collected using Nicolet 380 FTIR spectrometer at 1.0 cm−1 resolution with 16 scans per spectrum. The pH of the sample solution was varied (e.g., from 1.6 to 13.9, e.g., at 1.6 and 7.4, at 25° C.). Spectra for both the sample and the D2O were collected with the same procedure and the solvent spectra were subtracted from the sample spectra.

[0259]Absorptive 2D IR spectra were collected using a 2D IR spectrometer as described in detail previously (Chung, H. S., Khalil, M., Smith, A. W. & Tokmakoff, A. Transient two-dimensional IR spectrometer for probing nanosecond temperature-jump kinetics. Rev. Sci. Instrum...

example 2

Mutagenesis of KP1212 Depends on pH

[0262]The M13 single-stranded genomes, containing one KP1212 base at a specific site were constructed and purified as previously reported (Li, Fedeles, Singh, Peng et al, 2014, Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine, Proc. Natl. Acad. Sci. U.S.A. 111, E3252-3259).

[0263]Primer extension reactions at various pHs were carried out as follows: 100 fmol extension primer (5′-CGTGATCATGCGCAGACTGACATCATGTGTAAAACGACGGCC AGTGAATTGGA-3′) were annealed to 100 fmol M13 genome by heating the mixture at 80° C. for 5 min followed by a slow (0.1° C. / s) cooling to 4° C. The primer was extended by 2.5 U of a suitable polymerase (for example Klenow) in a solution containing 50 mM phosphate buffer (pH adjusted from 5.5-8.5 in 0.5 increments), 100 mM K+ (adjusted with KCl), 10 mM Mg2+, 1 mM DTT and 125 μM of each of the four dNTPs for 4 h at 30° C. The resulting product was p...

example 3

Binding Isotope Effect (BIE) for Determining the Tautomeric Forms of a Ligand (OxyTPP) Bound to its Target Macromolecule (TPP Riboswitch)

[0266]Experimental method for using BIEs to determine tautomeric form of OxyTPP bound to the TPP riboswitch. The spectroscopic approaches described above allowed the full characterization of the tautomeric forms of nucleic acid base, nucleoside, nucleotide, and their analogs in the unbound form. Given the complexity of the nucleic acid polymers aptamer, these approaches could not be directly applied to determine the tautomeric form of OxyTPP bound to the riboswitch. To establish the tautomeric form of the bound OxyTPP, experimental binding isotope effects (BIEs) were used, which characterize the increase or decrease in binding upon substitution of an atom with its heavier isotope. BIEs are useful as they are sensitive to change in bond order between two equilibrium states and are influenced by alterations in vibrational frequencies between the boun...

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Abstract

The present disclosure provides nucleoside analogs of Formula (I) or (II). The nucleoside analogs are expected to show multiple tautomerism and may increase the mutation of an RNA and / or DNA (be mutagenic) of a virus or cancer cell. The multiple tautomerism and mutagenesis of the nucleoside analogs may be adjusted by substituting the nucleoside analogs with one or more electron-donating groups and / or electron-withdrawing groups to increase or decrease the pKa (e.g., to a pKa between 5.5 or 8.5). The present disclosure also provides pharmaceutical compositions and kits including the nucleoside analogs and methods of treating a viral infection (e.g., influenza, HIV infection, or hepatitis) or cancer using the nucleoside analogs, pharmaceutical compositions, or kits.

Description

RELATED APPLICATIONS[0001]The present application is a continuation of and claims priority under 35 U.S.C. §120 to U.S. Ser. No. 15 / 009,628, filed Jan. 28, 2016, which claims priority under 35 U.S.C. §119(e) to U.S. provisional patent application, U.S. Ser. No. 62 / 109,020, filed Jan. 28, 2015, each of which is incorporated herein by reference in its entirety.GOVERNMENT SUPPORT[0002]This invention was made with U.S. Government support under grant numbers R37 CA080024, P01 CA026731, and P30 ES002109, awarded by the National Institutes of Health, and under grant number CHE-1212557 awarded by the National Science Foundation. The U.S. Government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]A major obstacle for viral disease treatment is viral persistence, which makes many current anti-rival therapies only temporality effective. Using HIV / AIDS as an example, nucleoside / nucleotide analog reverse transcriptase (RT) inhibitors, such as AZT, are the most commonly used ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H19/12G01N21/3577C12Q1/68C07H19/23C07H19/173A61K31/708A61K31/7076C07H19/04A61K31/706G01N33/15A61K31/7052A61K31/7064A61K31/7068
CPCA61K31/7064A61K31/706A61K31/7076A61K31/708C07H19/04C07H19/173C07H19/23C12Q1/6811G01N21/3577G01N33/15C07H19/12A61K31/7068A61K31/7052A61K45/06A61P31/12A61P31/18A61P31/20A61P35/00
Inventor ESSIGMANN, JOHN M.TOKMAKOFF, ANDREIFEDELES, BOGDAN I.SINGH, VIPENDERPENG, CHUNTE
Owner MASSACHUSETTS INST OF TECH
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