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Cyclic Peptide Antiviral Agents and Methods Using Same

Inactive Publication Date: 2019-12-12
DREXEL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a new compound called a cyclic compound of formula (I) and its salt, solvate, enantiomer, or diastereoisomer. This patent also describes a pharmaceutical composition containing the compound and methods of treating, preventing, and reducing the risk of HIV-1 infection, as well as promoting viral dissolution and reducing viral entry into cells. The patent also describes a method of using a derivatized gold nanoparticle to generate a reaction system with the cyclic compound. Overall, the patent provides technical effects related to the use of a novel compound for treating and preventing HIV-1 infection.

Problems solved by technology

Unfortunately, existing entry inhibitors suffer from weak potency and toxicity issues.

Method used

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  • Cyclic Peptide Antiviral Agents and Methods Using Same
  • Cyclic Peptide Antiviral Agents and Methods Using Same
  • Cyclic Peptide Antiviral Agents and Methods Using Same

Examples

Experimental program
Comparison scheme
Effect test

example 1

ptides

[0180]Cyclic peptides of the invention can be prepared using intramolecular cyclization according to the methods disclosed in International Application Publication No. WO 2016 / 094518, which is incorporated herein by reference in its entirety.

Chemical Synthesis of cPTs (3-38):

[0181]Alkynes a10-a16 were synthesized from the corresponding benzyl bromides a1-a9 following the procedures previously described (Louvel, et al., 2013, J. Med. Chem. 56:9427-40). Alkynes a10-a16 were used in click reactions without purification, because they are volatile and unstable upon storage. Mass validation of all cPTs was performed using Thermo Scientific LTQ XL Ion Trap LC / MS (Table 4).

General Synthesis of Alkynes a9-a16:

[0182]To a solution of ethynyltrimethylsilane (40 mmol) in 20 mL THF at 0° C., was added i-PrMgCl (2 M solution in THF) dropwise, and the mixture was stirred at 0° C. for 30 min, and allowed to warm up to r.t. for 30 min. CuBr (6 mmol) was added, and the mixture was stirred at r.t...

example 3

n of HIV-1 gp120 and Soluble CD4 Proteins

Reagents:

[0187]Escherichia coli strain Stbl2 cells were products of Novagen Inc. (Madison, Wis.). DNA plasmids encoding BaL.01 gp160 and NL4-3R-E-Luc+ were obtained from the NIH AIDS Reagent Program, Division of AIDS, NIAID. pcDNA3.1 vector carrying CD4 was a gift from Navid Madani. 17b IgG was purchased from Strategic Diagnostics Inc. (Newark, Del.). All other reagents used were of the highest analytical grade available.

Expression and Purification of Wild-Type gp120YU-2:

[0188]The DNA for gp120YU-2 in pcDNA3.1 vector for transient transfection was purified using a Qiagen MaxiPrep kit (Qiagen) after transforming into Stbl2 competent cells. The purified DNA encoding gp120 YU-2 was transfected into HEK 293F cells according to manufacturer's protocol (Invitrogen). Five days after transfection was initiated, cells were harvested and spun down (3000 RPM), and the supernatant was filtered through 0.2 m filters. Purification was performed over a 17b ...

example 4

n of HIV-1 gp120 Proteins

Surface Plasmon Resonance (SPR) Assays:

[0190]SPR experiments are performed on a Biacore 3000 optical biosensor (GE Healthcare). All experiments are carried out at 25° C. using standard PBS buffer pH=7.4 with 0.005% surfactant Tween and 2% DMSO.

[0191]Three flow cells in the CM5 chip were used for amine coupling of different ligands through standard 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide (EDC) / N-hydroxysuccinamide (NHS) chemistry. Flow cell 1 containing 2000 RUs of immobilized antibody 2B6R (α-human IL5R) served as a negative control for flow cells 2 and 3 each of which contained 2000 RUs of immobilized CD4 and 17b respectively.

[0192]For kinetic analyses, typically 2000-3000 RUs of protein reagents are immobilized on SPR chips, and analytes are passed over the surface at 50-100 μL / min. Surface regeneration is achieved by a 5 μL injection of 10 mM HCl solution at 100 μL / min. Analysis of peptide-mediated inhibition of gp120 binding to sCD4 and mAb 17b ...

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Abstract

The present invention includes novel cyclic peptides of formula (I). The present invention further includes novel cyclic peptides conjugated with a gold nanoparticle, and methods of using the same. The invention further provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one cyclic compound of the invention. The invention further provides a method of treating, reducing, or preventing HIV-1 infection in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of the invention.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Applications No. 62 / 394,494, filed Sep. 14, 2016, and No. 62 / 526,179, filed Jun. 28, 2017, all of which disclosures are incorporated herein by reference in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under GM056550 awarded by National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]The human immunodeficiency virus-1 (HIV-1) is responsible for a global epidemic, with over 33 million infected people worldwide. The lifecycle of HIV-1 has been extensively studied in the hope of identifying a therapeutic intervention that blocks viral transmission or viability. As an example, the Highly Active Anti-Retroviral Therapy (HAART) is a therapeutic approach targeting one or more stages of the HIV-1 life cycle. Favorable clinical results with HAAR...

Claims

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Application Information

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IPC IPC(8): C07K7/56A61K47/69A61P31/18
CPCA61K38/00A61K47/6929A61P31/18A61K47/6923C07K7/56A61K9/127C07K7/64A61K9/06A61K47/32C07K16/1063C07K2317/76
Inventor CHAIKEN, IRWIN M.AHMED, ADEL AHMED RASHAD
Owner DREXEL UNIV
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