University of California

University of Southern California

The Shriner's Hospital for Crippled Children

The General Hospital Corporation

Michael E Selsted

Dat Q Tran

Andre J Ouellette

James S Cullor

Robert I Lehrer

Jun Yuan

Justin B Schaal

Yi-Quan Tang

Virginia Basso

Tomas Ganz

Dat Tran

Christopher John Murphy

Michael Hugh Quinn

Ted W Reid

Samuel I Miller, Iii

Mark J Mannis

Kristien Mortelmans

Bradley A Foster

Larry L Chapoy

Leslie A Hokama

Daniel Tus&eacute;

Klara &Ouml;sapay

Patti Tran

A method is provided for a condition related to the activity of a protease through the administration of a θ-defensin, analog, or derivative is described. Suitable proteases include metalloproteases and cysteine proteases such as Cathepsin-C. The θ-defensin, analog, or derivative can be effectively administered parenterally, topically, or orally.

Compositions and methods for treatment of protease mediated disease

Novel peptide analogs of a θ-defensin have been developed that provide a biphasic effect in treating disseminated fungal disease and/or associated septic shock. These analogs are active at concentrations below those needed to provide a fungicidal effect, and function by initially mobilizing effector cells of the immune system to address the infective organism followed by regulation of the immune system to down regulate the inflammatory response. These novel θ-defensin analogs are protective at concentrations where naturally occurring θ-defensins have no apparent effect, and include a core set of structural and sequence features not found in native θ-defensins.

Compositions and methods for treatment of fungal infections

Peptide analogs of a θ-defensin have been developed that provide a biphasic effect in treating disseminated fungal disease and/or associated septic shock. These analogs are active at concentrations below those needed to provide a fungicidal effect, and function by initially mobilizing effector cells of the immune system to address the infective organism followed by regulation of the immune system to down regulate the inflammatory response. These θ-defensin analogs are protective at concentrations where naturally occurring θ-defensins have no apparent effect, and include a core set of structural and sequence features not found in native θ-defensins.

Novel peptide analogs of a &#x3b8;-defensin have been developed that provide a biphasic effect in treating disseminated fungal disease and/or associated septic shock. These analogs are active at concentrations below those needed to provide a fungicidal effect, and function by initially mobilizing effector cells of the immune system to address the infective organism followed by regulation of the immune system to down regulate the inflammatory response. These novel &#x3b8;-defensin analogs are protective at concentrations where naturally occurring &#x3b8;-defensins have no apparent effect, and include a core set of structural and sequence features not found in native &#x3b8;-defensins.

Novel peptide analogs of a &#x3b8;-defensin have been developed that provide a biphasic effect in treating infection and/or sepsis. These analogs are active at concentrations below those needed to provide a bactericidal or bacteriostatic effect, and function by initially recruiting effector cells of the immune system to address the infective organism followed by regulation of the immune system to down regulate the inflammatory response characteristic of sepsis and septic shock. These novel &#x3b8;-defensin analogs are protective at concentrations where naturally occurring &#x3b8;-defensins have no apparent effect, and include a core set of structural and sequence features not found in native &#x3b8;-defensin.

Theta defensin analogs

A method is provided for treating bowel disease related to the activity of TNF-&#x3b1;, through the administration of a &#x3b8;-defensin, analog, or derivative. Such a &#x3b8;-defensin, analog, or derivative can be effectively administered parenterally, topically, or orally. The &#x3b8;-defensin, analog, or derivative can be selected to additionally inhibit ADAM-10 activity.

Compositions and method for treatment of inflammatory bowel disease

Drug compositions for treatment of one or more inflammatory conditions can includes at least one of a &#x3b8;-defensin, analog or derivative thereof. Inventive methods include researching &#x3b8;-defensins, analogs or derivatives thereof for their efficacy with respect to anti-inflammatory effects, and providing such compositions to the marketplace for the purpose of treating inflammatory conditions. Of particular interest are drug compositions effective to produce clinically relevant inhibition of tumor necrosis factor alpha (TNF-&#x3b1;)-converting enzyme (TACE) or other proinflammatory proteases, and/or sheddases. it is contemplated that preferred compositions can be used to treat rheumatoid arthritis, inflammatory bowel disease, and other chronic inflammatory diseases, autoimmune diseases, cancer, and Alzheimer's, osteoarthritis, inflammation-related neurodegenerative and other inflammation-related diseases.

Blockade of inflammatory proteases with cyclic peptides

A method is provided for inhibiting TACE activity in a human subject, through the administration of a &#x3b8;-defensin, analog, or derivative. Such a &#x3b8;-defensin, analog, or derivative can be effectively administered parenterally, topically, or orally. The &#x3b8;-defensin, analog, or derivative can be selected to additionally inhibit ADAM-10 activity.

Inhibition of tace activity with cyclic peptides

The invention provides theta defensin analogs having antimicrobial activity. The invention also provides a method of reducing or inhibiting growth or survival of a microorganism in an environment capable of sustaining the growth or survival of the microorganism, comprising administering an effective amount of a theta defensin analog to the environment, thereby reducing or inhibiting the growth or survival of the microorganism.

Antimicrobial theta defensins, analogs thereof, and methods of use

The present invention relates to an isolated cyclic peptide, theta defensin, having antimicrobial activity, and to theta defensin analogs. A theta defensin can have the amino acid sequence Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa1-Xaa6-Xaa4-Xaa4-Xaa1-Xaa1-Xaa6-Xaa4-Xaa5-Xaa1-Xaa3-Xaa7-Xaa8, wherein Xaa1 to Xaa8 are defined; wherein Xaa1 can be linked through a peptide bond to Xaa8; and wherein crosslinks can be formed between Xaa3 and Xaa3, between Xaa5 and Xaa5, and between Xaa7 and Xaa7. For example, the invention provides a theta defensin having the amino acid sequence Gly-Phe-Cys-Arg-Cys-Leu-Cys-Arg-Arg-Gly-Val-Cys-Arg-Cys-Ile-Cys-Thr-Arg (SEQ ID NO:1), wherein the Gly at position 1 (Gly-1) is linked through a peptide bond to Arg-18, and wherein disulfide bonds are present between Cys-3 and Cys-16, between Cys-5 and Cys-14, and between Cys-7 and Cys-12. The invention also provides nucleic acids encoding theta defensins and antibodies that specifically bind a theta defensin. In addition, the invention relates to methods of using theta defensin to reduce or inhibit microbial growth or survival.

Antimicrobial theta defensins and methods of using same

The present invention relates to an isolated cyclic peptide, theta defensin, having antimicrobial activity, and to theta defensin analogs. A theta defensin can have the amino acid sequence Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa1-Xaa6-Xaa4-Xaa4-Xaa1-Xaa1-Xaa6-Xaa4-Xaa5-Xaa1-Xaa3-Xaa7-Xaa5, wherein Xaa1 to Xaa8 are defined; wherein Xaa1 can be linked through a peptide bond to Xaa8; and wherein crosslinks can be formed between Xaa3 and Xaa3, between Xaa5 and Xaa5, and between Xaa7 and Xaa7. For example, the invention provides a theta defensin having the amino acid sequence Gly-Phe-Cys-Arg-Cys-Leu-Cys-Arg-Arg-Gly-Val-Cys-Arg-Cys-Ile-Cys-Thr-Arg (SEQ ID NO:1), wherein the Gly at position 1 (Gly-1) is linked through a peptide bond to Arg-18, and wherein disulfide bonds are present between Cys-3 and Cys-16, between Cys-5 and Cys-14, and between Cys-7 and Cys-12. The invention also relates to antibodies that specifically bind a theta defensin and to isolated nucleic acid molecules encoding a theta defensin. In addition, the invention relates to methods of using theta defensin or a theta defensin analog to reduce or inhibit microbial growth or survival in an environment capable of sustaining microbial growth or survival by contacting the environment with the theta defensin.

The present invention relates to analogs of indolicidin, which is a naturally occurring peptide having the amino acid sequence Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-NH (&ldquo;Indol 1-13;&rdquo; SEQ ID NO: 1). The indolicidin analogs of the invention include, for example, analogs such as Indol 2-13 (SEQ ID NO: 2) and Indol 3-13 (SEQ ID NO: 3), which are truncated at the amino terminus by one and two amino acids, respectively, as compared to Indol 1-13 (SEQ ID NO: 1); analogs in which at least one Trp residue in an amino terminal truncated indolicidin analog is replaced by a Phe residue (&ldquo;Indol/F&rdquo;) analogs&rdquo;); indolicidin analogs comprising, at the carboxy terminus, a homoserine residue; and fusion polypeptides comprising an indolicidin analog. In addition, the invention provides nucleic acid molecules encoding the indolicidin analogs of the invention or precursors of such analogs. The invention also relates to methods of using the indolicidin analogs to reduce or inhibit microbial growth or survival by contacting an environment capable of sustaining microbial growth with the indolicidin analog.

Indolicidin analogs and methods of using same

Novel antimicrobial peptides from bovine and murine neutrophils are provided. The peptides, designated bovine granulocyte peptide A (BGP-A) and murine granulocyte peptide A (MGP-A) were purified to homogeneity from peripheral blood granulocytes. The amino acid and nucleotide sequence of BGP-A and MGP-A are also provided. A synthetic version of BGP-A and MGP-A is also provided. The purified BGP-A peptide is shown to have antimicrobial activity indistinguishable from that of natural BGP-A. Synthetic carboxamidated analogs of BGP-A (BGP-A-amide) and MGP-A (MGP-A-amide) are also provided.

Antimicrobial peptides and methods of use

The present invention relates to analogs of indolicidin, which is a naturally occurring peptide having the amino acid sequence Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-NH (&ldquo;Indol 1-13;&rdquo; SEQ ID NO: 1). The indolicidin analogs of the invention include, for example, analogs such as Indol 2-13 (SEQ ID NO: 2) and Indol 3-13 (SEQ ID NO: 3), which are truncated at the amino terminus by one and two amino acids, respectively, as compared to Indol 1-13 (SEQ ID NO: 1); analogs in which at least one Trp residue in an amino terminal truncated indolicidin analog is replaced by a Phe residue (&ldquo;Indol/F&rdquo;) &ldquo;analogs&rdquo;); indolicidin analogs comprising, at the carboxy terminus, a homoserine residue; and fusion polypeptides comprising an indolicidin analog. In addition, the invention provides nucleic acid molecules encoding the indolicidin analogs of the invention or precursors of such analogs. The invention also relates to methods of using the indolicidin analogs to reduce or inhibit microbial growth or survival by contacting an environment capable of sustaining microbial growth with the indolicidin analog.

Growing community of inventors

Pasadena, CA, United States of America

Michael E Selsted