New designs of arginase inhibitors as therapeutic and diagnostic agents
Researchers in the Christianson Lab have designed arginase inhibitors that bind to arginase I and II, and conducted structural analyses of several three-dimensional crystal structures with arginase-inhibitor complexes. Inhibiting arginase enhances nitric oxide-dependent smooth muscle relaxation, including gastrointestinal, airway, and genital smooth muscle. Therefore, arginase inhibitors can be used to treat allergen-induced asthma, chronic obstructive pulmonary disease (COPD) pulmonary hypertension, erectile dysfunction, and premature labor. Additionally, inhibiting arginase can enhance the nitric oxide-dependent tumor-killing properties of white blood cells. Thus, arginase inhibitors can be used in cancer immunotherapy.
These new structures provide enhanced flexibility, stability, and solubility compared to existing parent compounds (e.g. ABH, BEC, nor-NOHA) that inhibit arginase.
David W. Christianson, Roy and Diana Vagelos Professor in Chemistry and Chemical Biology
- R group of inhibitor can be highly varied to include polar and nonpolar substituents, halogens
- Aliphatic or aromatic linkages with peptides, peptidomimetics, or carbohydrates
- Compounds bind with higher affinity than parent molecules
- Alter pharmaceutically relevant properties, including crystal phase stability, water solubility, and lipophilicity
- Arginase inhibitors can be used for treatment of asthma/COPD, diabetes, hypertension, and sexual dysfunction
- Spectroscopic probe when attached to fluorescent molecule or NMR/MRI probe
- Diagnostic tool for determination of arginase overexpression as associated with asthma, cancer, or bacterial infections (H. pylori)
Stage of Development:
- Di Costanzo et al. Archives of Biochem and Biophys, 2010, 496(2), p. 101-108.
- Di Costanzo et al. PNAS, 2009, 102(37), p. 13058-13063.
- Kim et al. J. of Applied Physiology, 2009, 107(4), p. 1249-1257.
- Christianson et al. Accounts of Chem Research, 2005, 38(3), p. 191-201.
Docket # U4656, K1661