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HYDROGEN-BOND SURROGATE PEPTIDES AND PEPTIDOMIMETICS FOR p53 REACTIVATION

a technology of p53 and surrogate peptides, which is applied in the direction of peptides, drug compositions, peptides, etc., can solve the problems of inability to recommend hpv vaccination for adults, poor vaccine uptake at 2%, and no clinical evidence to support, etc., to promote a pleiotropic, anti-cancer effect, and dramatic potentiation of the efficacy of cis-platinum

Inactive Publication Date: 2014-07-24
THE OHIO STATE UNIV RES FOUND +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a new way to reactivate p53 in HPV-positive HNSCC (a type of cancer) by blocking the interaction between E6 and p300. This is done by using a small molecule called CH1 domain inhibitor (CH1iB) which promotes a pleiotropic anti-cancer effect and reduces the cancer-initiating cell population. The study also shows that CH1iB can enhance the efficacy of cis-platinum, a chemotherapy drug commonly used for HNSCC. Overall, this approach offers a promising druggable solution to treat HPV-positive carcinomas.

Problems solved by technology

It is assumed that the HPV vaccine will protect against HPV-positive HNSCC; however, there is no clinical evidence to support this expectation.
Gardasil was approved for males, 9 to 26 years old, in 2009; however, vaccine uptake was reported to be extremely poor at 2% (Reiter et al., “HPV Vaccine and Adolescent Males,”Vaccine 29(34):5595-602 (2012)).
HPV vaccination is not recommended for adults >26 years old since these individuals are likely to be exposed to high-risk HPV already.
Therefore, several generations of individuals already exposed to high-risk HPV or are >26 years old will not be vaccinated routinely or even if vaccinated will have minimal protection against HPV-positive carcinomas, including HNSCC.

Method used

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  • HYDROGEN-BOND SURROGATE PEPTIDES AND PEPTIDOMIMETICS FOR p53 REACTIVATION
  • HYDROGEN-BOND SURROGATE PEPTIDES AND PEPTIDOMIMETICS FOR p53 REACTIVATION
  • HYDROGEN-BOND SURROGATE PEPTIDES AND PEPTIDOMIMETICS FOR p53 REACTIVATION

Examples

Experimental program
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Effect test

example 1

Materials and Methods: Cell Lines

[0229]UMSCC47 and UMSCC74A were obtained from Dr. Thomas Carey at the University of Michigan. UPCI:SCC090 was provided by Dr. Susanne Gollin at the University of Pittsburgh (White et al., “The Influence of Clinical and Demographic Risk Factors on the Establishment of Head and Neck Squamous Cell Carcinoma Cell Lines,”Oral Oncol. 43(7):701-12 (2007), which is hereby incorporated by reference in its entirety). UMSCC47, UMSCC74A, and UPCI:SCC090 cells were grown in DMEM containing 10% FBS, 2 mM glutamine, 100 mg / mL streptomycin and 100 U / mL penicillin and maintained in a humidified atmosphere of 5% CO2 at 37° C.

example 2

Materials and Methods: Plasmid Construction and Transfection

[0230]The CH1 domain of p300 (nucleotides 332-417) was amplified by PCR (forward primer: 5′-GGATCCATGCCAGAGAAGCGCAAGCTCATCCAGC-3′; reverse primer: 5′-CTCGAGATCACCAGCATTTTTGAGGGGGAGACAC-3′) and inserted into pcDNA3.1 between the BamHI and Xhol restriction enzyme sites. UMSCC47, UMUPCI:SCC090, and UMSCC74A cells were transfected with pcDNA3.1 / empty or pcDNA3.1 / CH1 using Lipofectamine2000 (Invitrogen, Carlsbad, Calif.). Stable polyclonal populations were selected and maintained in the presence of G418 (Invitrogen).

example 3

Materials and Methods: Western Blot

[0231]Whole cell lysates were mixed with Laemmli loading buffer, boiled, separated by SDS-PAGE, and transferred to a nitrocellulose membrane. Subsequently, immunoblot analyses were performed using antibodies specific to V5 (Invitrogen), p53 (sc-126, Santa Cruz Biotechnology, Santa Cruz, Calif.), or acetylated[K382]-p53 (2525, Cell Signaling Technology). The signal was developed using the SuperSignal Western Blotting Kit (Pierce, Rockford, Ill.).

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Abstract

The present invention relates to peptidomimetics for reactivating p53. Methods of using the peptidomimetics are also disclosed.

Description

[0001]This application claims the priority benefit of U.S. Provisional Patent Application Ser. No. 61 / 754,574, filed Jan. 19, 2013, and U.S. Provisional Patent Application Ser. No. 61 / 874,190, filed Sep. 5, 2013, each of which is hereby incorporated by reference in its entirety.[0002]This invention was made with government support under grant numbers R01CA135096 and R01GM073943 awarded by the National Institutes of Health. The government has certain rights in this invention.FIELD OF THE INVENTION[0003]This invention is directed generally to artificially constrained peptides and peptidomimetics for targeting the E6-p300 interaction.BACKGROUND OF THE INVENTION[0004]Human papillomaviruses (HPV) are small, double-stranded DNA viruses that infect the epithelium. More than 100 HPV types have been identified. They are differentiated by the genetic sequence of the outer capsid protein L1. Most HPV types infect the cutaneous epithelium and cause common skin warts. About 40 types infect the m...

Claims

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Application Information

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IPC IPC(8): C07K7/56A61K33/24A61K38/12A61K33/243A61K38/08
CPCC07K7/56A61K38/12A61K33/24C07K7/64A61K38/00A61K45/06A61K38/08A61K33/243A61K2300/00
Inventor ARORA, PARAMJIT S.PAN, QUINTINMAPP, ANNA
Owner THE OHIO STATE UNIV RES FOUND