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Inhibition of viral infection and spread with viral and RhoA-derived peptides

a technology of rsv and peptides, which is applied in the direction of peptides, antibody medical ingredients, peptide sources, etc., can solve the problems of rsv not preventing illness, recurrent wheezing, and severity decline, and achieve rapid screening and screening

Inactive Publication Date: 2005-10-13
VANDERBILT UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides isolated peptides and antibodies that inhibit the infection of cells by enveloped viruses, such as respiratory syncytial virus and human immunodeficiency virus. These peptides and antibodies target the viral fusion protein that allows the virus to enter susceptible cells. The peptides are derived from the mammalian RhoA protein sequence and are administered to a subject at risk for viral infection or in whom active infection has been established to inhibit viral entry and cell-to-cell spread of the virus. The peptides can be administered through various routes, including intravenously, orally, nasally, and topically. The invention also provides a method for identifying RhoA-binding regions in viral fusion proteins and screening blood and tissue samples for the presence of viruses that may be susceptible to inhibition by the peptides and antibodies.

Problems solved by technology

Exaggerated RSV IgE response during RSV bronchiolitis in infancy has also been associated with the widespread problem of recurrent wheezing in early childhood.
Although disease severity declines with repeated infection, previous infection with RSV does not prevent illness in subsequent infections.
Live virus vaccines have generally proven to be inadequately immunogenic by the time they have been attenuated to a sufficient level to produce no clinical illness.
High-risk infants are treated with immunoglobulin (IG) to protect against RSV, but intravenous RSV IG is very expensive and administration requires a monthly infusion lasting 7 hours or more to maintain acceptable antibody titers.
Vaccine development for the prevention of HIV infection, and subsequent development of acquired immunodeficiency syndrome (AIDS), has been less successful than had earlier been anticipated.
The present generation of gp120 subunit vaccines have not been shown to induce relevant antibody or cell-mediated immune responses of significant potency, and their performance in Phase I / II trials has been disappointing.
Contributing to the difficulties in vaccine development are the characteristics of the virus, including poor immunogenicity of the HIV envelope glycoproteins and their resistance to neutralizing antibodies, the extensive variation in the viral genome, and the ability of the virus to become integrated into the host genome of immune cells (Agosto et al.).
Even with this very aggressive treatment regimen, however, unintegrated HIV-1 DNA in cells from patients receiving HAART treatment has been found, suggesting that a low level of viral replication may continue and contribute to the maintenance of a reservoir of HIV-infected cells (Chun et al.).
Blocking the binding of the virus also has proven to be more difficult than anticipated.
Early experiments had shown that HIV's primary receptor, CD4, was not itself sufficient to promote viral entry into a susceptible cell.
Subsequently, coreceptors were identified, making earlier hopes to develop drugs to block viral attachment more difficult to realize.

Method used

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  • Inhibition of viral infection and spread with viral and RhoA-derived peptides
  • Inhibition of viral infection and spread with viral and RhoA-derived peptides
  • Inhibition of viral infection and spread with viral and RhoA-derived peptides

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Viruses and Cells

[0118] The A2 strain of RSV was provided by Dr. R. Chanock, National Institutes of Health, Bethesda, Maryland. Virus stocks were prepared as described by Graham et al. HEp-2 cells were maintained in Eagle's minimal essential media (MEM) supplemented with glutamine, gentamicin, penicillin G, and 10% fetal bovine serum.

[0119] The MT-2 cell line is a fusion susceptible cell line used as the target cell for the HIV assays. It is a CD4+ T-lymphoblastoid cell line derived from HTLV-1 transformed cord blood lymphocytes (Miyoshi et al.). The subclone of MT-2 cells used for the experiments was a gift from Doug Richman, San Diego Veterans Administration Hospital. MT-2 cells were maintained in RPMI-1640 supplemented with 12% fetal bovine serum (FBC) and 50 mg gentamicin / ml.

Yeast Two-Hybrid System

[0120] The DNA sequences encoding the respiratory syncytial virus F glycoprotein with and without the transmembrane and cytoplasmic domains were PCR amplified and cloned into Eco...

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Abstract

Isolated peptides, peptidomimetics, and antibodies which bind to the viral fusion protein binding domain of the RhoA protein or the RhoA binding domain of a viral fusion protein are useful for inhibiting infection in susceptible cells, in vitro and in vivo. Among these viruses are the Paramyxovirus respiratory syncytial virus (RSV) and the Lentivirus human immunodeficiency virus (HIV).

Description

[0001] This application claims benefit of co-pending Provisional U.S. patent application Ser. No. 60 / 087,955 filed Jun. 4, 1998, entitled “Inhibition of Paramyxovirus and Lentivirus Infection and Spread with RhoA-Derived Peptides.”STATEMENT OF GOVERNMENT RIGHTS [0002] A portion of the work described herein was funded in part by National Institutes of Health Grant Number RO1-AI-33933. The U.S. Government may therefore have certain rights relating to this invention.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The present invention relates to methods of inhibiting viral entry and spread in vivo and in vitro. The invention further relates to isolated peptides from a mammalian Rho protein which have been found by the inventors to be useful for inhibiting entry of enveloped viruses, specifically paramyxoviruses and lentiviruses, into susceptible cells. In particular embodiments, the invention also relates to methods of preventing infection by enveloped viruses. Thes...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00C07K14/135C07K14/16C07K14/705C07K16/28C12N15/12
CPCA61K39/00A61K2039/525C07K14/005C12N2760/18522C07K16/28C12N2740/16122C07K14/705
Inventor GRAHAM, BARNEYPATSEY, MANOJ
Owner VANDERBILT UNIV
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