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Anti-heparan sulfate peptides that block herpes simplex virus infection in vivo

a technology of anti-heparan sulfate and peptides, which is applied in the direction of peptides/protein ingredients, peptides, immunoglobulins, etc., can solve the problems of inability to cure the subject of infection, the severity of hsv outbreak, and the severity of infection, so as to inhibit viral infection and/or receptor-mediated cell-to-cell fusion, and strong herpesvirus entry-inhibiting activities

Inactive Publication Date: 2013-07-25
THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about peptides that can prevent viral infections and cell-to-cell fusion. Specifically, the patent is about two groups of cationic peptides, designated G1 and G2, which are specific to herpesvirus and related viruses. These peptides have been shown to inhibit viral entry in animal models of infection. The patent also describes reverse-inverso peptides, which are forms of the original peptides with some amino acids in reverse order and / or chirality. These retro-inverso peptides may have enhanced properties for viral prevention and treatment, such as low immunogenicity and resistance to proteolysis. Overall, the patent presents a tool for combating viral infections and offers a new way to develop drugs for this purpose.

Problems solved by technology

Such infections may be especially severe in immunocompromised subjects.
Existing antiviral drugs can reduce the severity of HSV outbreaks, but cannot cure the subject of the infection.

Method used

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  • Anti-heparan sulfate peptides that block herpes simplex virus infection in vivo
  • Anti-heparan sulfate peptides that block herpes simplex virus infection in vivo
  • Anti-heparan sulfate peptides that block herpes simplex virus infection in vivo

Examples

Experimental program
Comparison scheme
Effect test

example 1

Experimental Procedures

[0125]Selection of Phages Against HS and 3-OS HS by Library Panning

[0126]A phage display library (PhD™-12) expressing 12-mer peptides fused to a minor coat protein (pIII) of a non-lytic bacteriophage (M13) was purchased from New England Biolabs (Cambridge, Mass.). A purified form of HS isolated from bovine kidney was purchased from Sigma. Soluble 3OS HS modified by 3-OST-3 was prepared as previously described. Tiwari et al., J. Gen. Virol. 88:1075-1079 (2007).

[0127]Screening of the phage display library was accomplished by an affinity selection (or bio-panning) process during which phage populations were selected for their ability to bind HS and 3OS HS (modified by 3-OST-3). Both targets at a concentration of 10 μg / ml were used for overnight coating of wells of 96 well plates (Nalge Nunc International, Naperville, Ill.) in a humidifier chamber at 4° C. The following day, the plates were blocked for 1 hr at room temperature with 5 mg / ml bovine serum albumin (BS...

example 2

Identification of HS and 3-OS HS Binding Peptides that Block HSV-1 Entry

[0150]Three rounds of screening of phages from a 12-mer peptide phage display library resulted in the enrichment of phages that specifically-bound to HS and / or to 3-OS HS. Peptide sequences from individual plaques were deduced by determining the nucleotide sequences of the portion of the phage genome that encoded them. The predicted peptide sequences of about 200 plaques were determined and sorted into two groups on the basis of their targets. A frequently repeating peptide sequence from each group was subsequently selected for further characterization. The two most frequently isolated peptide sequences LRSRTKIIRIRH (designated G1 for HS binding group 1) and MPRRRRIRRRQK (designated G2 for 3-OS HS binding group 2) were synthesized and examined for each peptide's ability to inhibit HSV-1 infection of 3-OST-3 (FIG. 1A), nectin-1 (FIG. 1B), and HVEM (FIG. 1C) expressing CHO-K1 cells. Cells were pre-incubated with G...

example 3

The Peptide Inhibitors are Also Active Against a Variety of HSV-1 Strains

[0154]This Example demonstrates that the inhibitory effect of the G2 peptide is not limited by viral strain or serotype.

[0155]The anti-HSV properties of the G1 and G2 peptides were evaluated against common strains of HSV-1 and HSV-2 (i.e., strains F, G, Hfem, MP, KOS, and 17). Dean et al., Virology 199:67-80 (1994). 3-OST-3 expressing CHO Ig8 reporter cells were used that express β-galactosidase upon viral entry. Montgomery et al., Cell 87:427-436 (1996). Cells were pre-incubated with G1, G2, or control peptide (Cp) and subsequently infected with the viruses. G2 or Cp control at 0.5 mM concentration was incubated for 60 min at room temperature with a reporter CHO-Ig8 cells that express β-galactosidase upon HSV-1 entry. After incubation, the cells were infected with HSV-1 (Pal, 17, Hfm, F, KOS, and MP) and HSV-2 (G) strains at 25 pfu / cell for 6 hr at 37° C. Blockage of viral entry was measured by ONPG assay as d...

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Abstract

Provided are anti-heparan sulfate peptides and methods that employ those peptides for the prevention or treatment of viral infections, including herpesviral infections such as α-herpesviral, β-herpesviral, and γ-herpesviral infections, which are exemplified by HSV-1. CMV, and HHV-8 viral infections, respectively. Peptides may comprise at least 10 amino acids of the amino acid sequences XRXRXKXXRXRX (SEQ ID NO: 2), XRXRXXKXRXRX (SEQ ID NO: 8), XXRRRRXRRRXK (SEQ ID NO: 4), and / or KXRRRXRRRRXX (SEQ ID NO: 10), wherein X represents any amino acid. In some embodiments, peptides comprise at least 10 amino acids of the sequence LRSRTKIIRIRH (SEQ ID NO: 1), HRIRIIKTRSRL (SEQ ID NO: 7), MPRRRRIRRRQK (SEQ ID NO: 3), and / or KQRRRIRRRRM (SEQ ID NO: 9). Peptides may be coupled to one or more therapeutic compound(s) to generate peptide-therapeutic compound conjugates, wherein the therapeutic compound may be one or more of a nucleoside analog, an oligosaccharide, and a small molecule.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation-in-part of International Application No. PCT / US2011 / 052002, filed Sep. 16, 2011 and titled “Anti-Heparan Sulfate Peptides That Block Herpes Simplex Virus Infection In Vivo,” which claims the benefit of U.S. Provisional Patent Application No. 61 / 383,520, filed Sep. 16, 2010, and the present application also claims the benefit of U.S. Provisional Patent Application No. 61 / 651,643, filed May 25, 2012, the entire disclosures of which are hereby incorporated by reference in their entireties.GOVERNMENT SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under R01 Grant Nos. AI057860 awarded by the National Institutes of Health. The government has certain rights in the invention.SEQUENCE LISTING[0003]The present application includes a Sequence Listing in electronic format as a text file entitled “Sequence_Listing_DA015CIP.txt” which was created on Mar. 14, 2013, and whi...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K7/06
CPCC07K7/06C07K7/08A61K47/646
Inventor SHUKLA, DEEPAKTIWARI, VAIBHAV
Owner THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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