Cyclic Peptide Antiviral Agents and Methods Using Same

a technology of cyclic peptides and antiviral agents, applied in the direction of peptides, peptide/protein ingredients, immunoglobulins, etc., can solve the problems of weak potency and toxicity of existing entry inhibitors, and achieve the effects of reducing the risk of hiv-1 infection, promoting virolysis of a virus, and treating, reducing or preventing hiv-1 infection

Pending Publication Date: 2022-06-30
DREXEL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0008]The invention provides a cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof. 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. The invention further provides a method of reducing the risk of HIV-1 infection in a mammal at risk of HIV-1 exposure, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of the invention. The invention further provides a method of promoting virolysis of a virus, the method comprising contacting the virus with an effective amount of at least one cyclic compound of the invention, wherein P1 is not absent. The invention further provides a method of reducing the rate of or preventing entry of a virus into a cell of a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of the invention. The invention further provides a method of preparing a derivatized gold nanoparticle, the method comprising contacting the nanoparticle with at least one cyclic compound of the invention to generate a reaction system; and isolating the derivatized gold nanoparticle from the reaction system.

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

[0181]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)

[0182]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

[0183]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 2

us Production, Antiviral Assay and Cytotoxicity Assay

[0185]Pseudoviruses were produced as previously described (Umashankara, et al., 2010, ChemMedChem 5:1871-9). Briefly, HEK 293T cells (3×106) were co-transfected with 4 μg of BaL.01 gp160 plasmid and 8 μg of NL4-3R-E-Luc+ core DNA (obtained from the NIH AIDS Reagent Program), using Polyethyleneimine (PEI) as a transfection vehicle. After 72 hours, the supernatant containing virus was collected and filtered using a 0.45 μm syringe filter (Corning). The supernatant was then loaded on a 10 ml Iodixanol gradient; 6%-20% (Optiprep, Sigma Aldrich) and centrifuged on SW41Ti rotor (Beckman Coulter) at 30,000 RPM for 2 hours at 4° C. Virus samples were pooled from fractions 6 through 9 in 1 ml aliquots and diluted in serum free media, before storage in −80° C. All batches of virus were titrated for infectivity and p24 content immediately after production.

[0186]Pseudoviral infection assays were carried out as previously described (Emileh, et...

example 3

n of HIV-1 gp120 and Soluble CD4 Proteins Reagents

[0189]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

[0190]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 μm filters. Purification was performed over a 17b ...

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Abstract

The present invention includes novel cyclic peptides, and methods of using the same. The present invention further includes novel cyclic peptides conjugated with a gold nanoparticle, and methods of using the same.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 16 / 331,861, filed Mar. 8, 2019, which is a 35 U.S.C. § 371 national phase application from, and claims priority to, International Application No. PCT / US2017 / 051380, filed Sep. 13, 2017, and published under PCT Article 21(2) in English, which 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 exte...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K7/56A61K47/69A61P31/18
CPCC07K7/56A61K47/6929A61K38/00A61P31/18A61K47/6923A61K9/127C07K7/64A61K9/06A61K47/32C07K16/1063C07K2317/76
Inventor CHAIKEN, IRWIN M.AHMED, ADEL AHMED RASHAD
Owner DREXEL UNIV
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