The Brigham and Women's Hospital, Inc.

Daniel Simon

Jonathan S Stamler

Joseph Loscalzo

David J Singel

Jeffrey M Drazen

Adam Slivka

Robert Brown

Harold A Chapman

Guo-Ping Shi

Peter Libby

Galina K Sukhova

Joeseph Loscalzo

Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: S-nitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoprotein; and S-nitroso-immunoglobulin. The invention also relates to therapeutic use of S-nitroso-protein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body. The invention also relates to the nitrosylation of oxygen, carbon and nitrogen moieties present on proteins and amino acids, and the use thereof to achieve the above physiological effects.

Nitrosylation of protein SH groups and amino acid residues as a therapeutic modality

The invention provides methods of treating and preventing vascular diseases, by inhibiting cysteine proteases active at sites of vascular injury, particularly cathepsins K and S, by administering cystatin C or TGF-&bgr; . Cystatin C is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Also provided is a method of diagnosing a patient at risk of, or with, vascular injury by detecting low levels of circulating cystatin C.

Methods of treating vascular disease associated with cystatin C deficiency

Nitrosylation of protein SH groups and amino acid residues as a

Methods of relaxing corpus cavernosum smooth muscle, treating disease states responsive to prevention or relaxation of undesirable contractions of corpus cavernosum smooth muscle and of treating male impotence by administering an S-nitrosothiol such as a low molecular weight S-nitrosothiol, S-nitroso-ACE-inhibitor or S-nitroso-protein.

Treatment of male impotence with s-nitrosylated compounds

S-nitrosothiols exert a potent relaxant effect, mediated both by guanylate cyclase, and a cGMP-independent mechanism, upon non-vascular smooth muscle. Such types of smooth muscle include airway, gastrointestinal, bladder, uterine and corpus cavernosal. Thus, S-nitrosothiols may be used for the treatment or prevention of disorders associated with relation of smooth muscle, such as airway obstruction, and other respiratory disorders, bladder dysfunction, premature labor and impotence. Additionally, S-nitrosothiols may be used to alleviate smooth muscle contraction and spasm, and thus facilitate procedures involving diagnostic instrumentation, such as endoscopy, bronchoscopy, laparoscopy and cystoscopy. S-nitrosothiols also increase the binding affinity between hemoglobin and oxygen, and therefore, may be used to improve hemoglobin-oxygen binding, and oxygen transport to bodily tissues.

S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof

S-nitrosothiols exert a potent relaxant effect, mediated both by guanylate cyclase, and a cGMP-independent mechanism, upon non-vascular smooth muscle. Such types of smooth muscle include airway, gastrointestinal, bladder, uterine and corpus cavernosal. Thus, S-nitrosothiols may be used for the treatment or prevention of disorders associated with relaxation of smooth muscle, such as airway obstruction, and other respiratory disorders, bladder dysfunction, premature labor and impotence. Additionally, S-nitrosothiols may be used to alleviate smooth muscle contraction and spasm, and thus facilitate procedures involving diagnostic instrumentation, such as endoscopy, bronchoscopy, laparoscopy and cystoscopy. S-nitrosothiols also increase the binding affinity between hemoglobin and oxygen, and therefore, may be used to improve hemoglobin-oxygen binding, and oxygen transport to bodily tissues.

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Waban, MA, United States of America

Daniel Simon