The United States of America, as Represented by the Secretary, Department of Health and Human Services

The United States of America as Represented by the Department of Health

University of Massachusetts

Joel Moss

Rodney L Levine

Maria S Nightingale

Linda Stevens

Toshiya Hirayama

Gregorino Paone

Akihiro Wada

Rita Bellis Bortell

Christelle Bourgeois

Mikako Tsuchiya

Koichi Mishima

James J Murtagh

Anna Zolkiewska

Shunya Oka

Tatsuyuki Takada

Ian Okazaki

Sally J Stanley

Jiro Kato

Lucia Monaco

Jianfeng Zhu

Arnold Kristof

Atsushi Kasamatsu

Disclosed herein are methods of treating a subject with pulmonary disease including administering to the subject a therapeutically effective amount of a polypeptide including at least one arginine residue susceptible to ADP-ribosylation and nicotinamide adenine dinucleotide (NAD). In some embodiments, the polypeptide and/or NAD is administered via inhalation. Also disclosed is a pharmaceutical composition including at least one polypeptide (such as HNP-1) and NAD. The disclosure also provides in vitro methods of producing a polypeptide with altered activity, including contacting the polypeptide with NAD and an arginine-specific mono-ADP-ribosyltransferase (for example, ART1) to produce a polypeptide including at least one ADP-ribosylated arginine residue, incubating the ADP-ribosylated polypeptide under conditions sufficient for conversion of at least one ADP-ribosylated arginine residue to ornithine, and isolating the ornithine-containing polypeptide. Methods of treating a subject with pulmonary disease including administering to the subject a therapeutically effective amount of a modified polypeptide (such as HNP-1) including at least one ornithine residue in place of an arginine residue are also disclosed.

Method for the treatment of pulmonary disease and method of producing proteins of use therein

This disclosure provides modified antimicrobial agents, for example modified defensin polypeptides. Compositions including a modified arginine residue, such as an ADP-ribosylated and/or ribosylated alpha defensin polypeptide, are provided. Also provided are methods of modulating an immune response using the modified defensin polypeptides. Methods are provided for modulating an antimicrobial activity and for inhibiting a cytotoxic activity. Also disclosed are methods for treating diseases in a subject that are associated with an immune response, such as inflammatory and pulmonary diseases, using the disclosed modified defensin polypeptides.

Modified defensins and their use

Disclosed herein are methods for suppressing an immune response in a subject, treating a neoplasm in a subject, or treating a fibroproliferative vascular disease in a subject, that includes administering to the subject a therapeutically effective amount of a 2-(4-piperazinyl)-substituted 4H-1-benzopyran-4-one compound, or a pharmaceutically acceptable salt thereof, having the structure of wherein the presence of each of Rand Ris optional and Rand Rare each independently selected from alkyl, substituted alkyl, heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, halogen, hydroxy, or amino.

Methods for suppressing an immune response or treating a proliferative disorder

A method is disclosed for producing a polypeptide with a modified activity or stability, by replacing an arginine residue capable of being ADP-ribosylated with a tryptophan or a phenylalanine. In one embodiment, compositions are provided that include polypeptides, such as alpha defensin, with arginine-to-tryptophan or arginine-to-phenylalanine substitutions, where the arginine residue is capable of being ADP-ribosylated. In another embodiment, methods are disclosed for modifying an immune response in a subject.

Tryptophan as a functional replacement for ADP-ribose-arginine in recombinant proteins

This disclosure provides methods for catalyzing the release of ADP-ribose from poly(ADP-ribose) or O-acetyl-ADP-ribose. Also provided are methods for modifying DNA repair or chromatin structure by introducing into the cell an agent that modifies the activity of an ARH3 polypeptide, or variant or fragment thereof. Further provided are methods for screening molecules involved in the poly(ADP-ribosyl)ation of proteins or O-acetyl-ADP-ribose content, and method for treating disorders by altering activity of an ARH3 protein.

ADP-ribosyl acceptor hydrolase 3 (ARH3) polypeptides and methods of use

This disclosure provides modified antimicrobial agents, for example modified defensin polypeptides. In one embodiment, compositions including a modified arginine residue, such as an ADP-ribosylated and/or ribosylated alpha defensin polypeptide, are provided. Also provided are methods of modulating an immune response using the modified defensin polypeptides. In one embodiment, a method is provided for modulating an antimicrobial activity. In another embodiment, a method is provided for inhibiting a cytotoxic activity. Also disclosed are methods for treating diseases in a subject that are associated with an immune response, such as inflammatory and pulmonary diseases, using the disclosed modified defensin polypeptides.

This invention relates to the identification and molecular characterization of NAD:arginine ADP-ribosyltransferases. Sequences from the rabbit skeletal muscle NAD:arginine ADP-ribosyltransferase and the human NAD:arginine ADP-ribosyltransferase are provided herein. Recombinant protein is expressed from a recombinant gene vector containing at least 15 continuous bases of genes encoding these sequences.

Mammalian muscle NAD: arginine ADP-ribosyltransferase

The present invention relates to the production of mammalian ADP-ribosylarginine hydrolases. These enzymes can be manufactured using recombinant DNA technology and are useful in regulation of proteins involved in key metabolic pathways.

Clones encoding mammalian ADP-ribosylarginine hydrolases

The invention provides a method for detecting the presence of ARD 1 protein in a sample. The method includes the steps of providing labeled or immobilized anti-ARD 1 antibody in a reaction zone, introducing sample into the reaction zone such that ARD 1 protein in the sample, if present, will react with said antibody to form an immunological complex, and detecting the formation of said immunological complex. Cells, nucleotide and amino acid sequences and vectors associated with ARD 1 are also described.

Growing community of inventors

Bethesda, MD, United States of America

Joel Moss