Description of Invention:
The present invention provides methods of inhibiting acetyletransferase enzymes, such as arylalkylamine-N-acetyltransferase (AANAT), by producing a bisubstrate inhibitor in a cell. AANAT catalyzes the transfer of acetyl groups from Acetyl coenzyme A (AcCoA) to substrates such as serotonin. Bisubstrate inhibitors are compounds which share characteristics of AcCoA and of the specific acetyl group acceptors. A highly potent bisubstrate inhibitor of AANAT is CoA-S-N-acetyltryptamine. That inhibitor may be formed in vitro by the reaction of alkylating derivatives of the acetyl acceptor and AcCoA. However, the inhibitor thus formed does not cross the cell membranes and is expensive to produce using AcCoA.
The present invention is based on the surprising discovery that a bisubstrate inhibitor which is specific for a particular acetyltransferase can be formed in a cell by introducing into the cell an alkylating derivative of an acetyl acceptor. Formation of the bisubstrate inhibitor occurs efficiently at very low concentrations of introduced drug because the enzyme to be inhibited positions and catalyzes the reactants favorably to form the inhibitor. The bisubstrate inhibitor is likely to accumulate in the cell because it is stable, highly charged and thus will not pass through cell membranes. The targeted acetyltransferase will thus be inhibited and therapeutic actions realized.
The varied actions of acetyltransferases in biochemical processes offer many potential therapeutic targets. Acetylation inactivates drugs and endogenous ligands so inhibitors could, for example, enhance the effectiveness of antibiotics where antibiotic resistance is due to a high level of acetylation. In the case of AANAT, acetylation inactivates serotonin and is the rate limiting step in the formation of melatonin. Inhibition of AANAT will thus decrease melatonin production and increase serotonin levels. Melatonin is a pineal hormone that has endocrinological, neurophysiological, and behavioral functions. Since melatonin and serotonin are implicated in several types of mood disorders, inhibition of AANAT could have valuable therapeutic uses. Specific inhibitors of melatonin synthesis are not yet available and serotonin antagonists have unacceptable side effects in many patients.
Inventors:
David C. Klein et al. (NICHD)
Patent Status:
DHHS Reference No. E-205-1999/0 --
U.S. Patent Application No. 09/374,742 filed 13 Aug 1999
PCT Application No. PCT/US00/21631 filed 08 Aug 2000, which published as WO 01/12185 on 22 Feb 2001
U.S. Patent Application No. 09/910,588 filed 20 Jul 2001
Licensing Status: In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.
For Additional Information Please Contact: Charlene A. Sydnor Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: 301/435-4689
Email: sydnorc@mail.nih.gov
Fax: 301/402-0220
