Methods and compositions using stearoyl-CoA desaturase to identify triglyceride reducing therapeutic agents
AssigneesXenon Pharmaceuticals Inc., Wisconsin Alumni Research Foundation, The University of British Columbia
InventorsMichael R. Hayden, Alison J. Brownlie, James M. Ntambi, Makoto Miyazaki, Mark P. Gray-Keller, Alan D. Attie
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Abstract
The use of screening assays based on the role of human stearoyl-CoA desaturase-1 (“hSCD1”) in human diseases, disorders or conditions relating to serum levels of triglyceride, VLDL, HDL, LDL, total cholesterol, or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, is disclosed. Also disclosed are conventions useful in the prevention and/or treatment of such diseases.
Claims118
A method for identifying, from a library of test compounds, a therapeutic agent which is useful in humans for the treatment of a disorder or condition relating to serum levels of triglyceride or VLDL comprising
- a) providing a screening assay having SCD1 biological activity;
- b) contacting said screening assay with a test compound;
- and
- c) subsequently measuring said biological activity;
- wherein a test compound which modulates said biological activity is said therapeutic agent, or an analog thereof.
A screening assay for identifying compounds useful in human for the treatment of a disorder or condition relating to serum levels of triglyceride, or VLDL, said screening assay comprising
- a) a screening assay having SCD1 biological activity;
- wherein a test compound which modulates said SCD1 biological activity in said screening assay is a compound, or an analog thereof, which is useful for said treatment.
A method for identifying, from a library of test compounds, a therapeutic agent which is useful in humans for the treatment of a disorder or condition relating to serum levels of triglyceride or VLDL, comprising
- a) an assay having measurable SCD1 biological activity;
- wherein a test compound that modulates SCD1 biological activity upon contact with said assay is said therapeutic agent or an analog thereof.
A cell line containing a recombinant SCD1 protein.
A recombinant cell line comprising the SCD1 promoter nucleic acid sequence of SEQ ID No. 1 operably linked to a reporter gene construct.
An isolated stearoyl-CoA desaturase (SCD) nucleic acid encoded by the polynucleotide sequence comprising SEQ ID No. [SCD1 cDNA]
A reporter gene construct comprising the SCD1 promoter nucleic acid sequence of SEQ ID No. 1 operably linked to a reporter gene.
An isolated stearoyl-CoA desaturase protein.
A method of treating a disease or condition in a human selected from among a disorder or condition relating to serum levels of triglyceride or VLDL, said method consisting essentially of inhibition of the activity of SCD1 protein in said human.
A modulator of SCD1 biological activity which is useful in humans for treatment of a disorder or condition relating to serum levels of triglyceride or VLDL, identified by a screening assay wherein said modulator detectably modulates SCD1 biological activity.
A composition which is useful in humans for treatment of a disorder or condition relating to serum levels of triglyceride or VLDL, first identified by a screening assay wherein said composition modulates the biological activity of SCD1.
A method for identifying, from a library of test compounds, a therapeutic agent which is useful in humans for the treatment of a disorder or condition relating to serum levels of triglyceride, VLDL, HDL, LDL, total cholesterol, reverse cholesterol transport or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, comprising
- a) providing a screening assay having a measurable biological activity of a vertebrate delta-9 stearoyl-CoA desaturase;
- b) contacting said screening assay with a test compound;
- and
- c) subsequently measuring said biological activity;
- wherein a test compound which modulates said biological activity is said therapeutic agent, or an analog thereof.
A method for up-regulating the ABCA1 gene in an individual comprising the step of administering to that individual an agent which lowers the level of activity of stearoyl-CoA desaturase (SCD1) protein in that individual.
A method for elevating high density lipoprotein (HDL) particles in an individual comprising the step of administering to that individual an inhibitor of an SCD1 protein.
A method for reducing very low density lipoprotein (VLDL) particles in an individual comprising the step of administering to that individual an inhibitor of an SCD1 protein.
A method for reducing plasma triglycerides particles in an individual comprising the step of administering to that individual an inhibitor of an SCD1 protein.
A method for enhancing the cellular efflux of phospholipids and/or cholesterol in an individual comprising the step of administering to that individual an inhibitor of an SCD1 protein.
A method for inhibiting atherosclerosis in an individual comprising the step of administering to that individual an inhibitor of an SCD1 protein.
A method for treating diabetes and insulin resistance in an individual comprising the step of administering to that individual an inhibitor of an SCD1 protein expression or activity.
A method of testing compounds for their effects on ABCA1 activity comprising the steps of feeding an amount of the test compounds to s subject and monitoring the effect on the level of SCD1 activity in the subject.
A method for identifying, from a library of test compounds, a therapeutic agent which is useful in humans for the treatment of a disorder or condition relating to serum levels of HDL, LDL, total cholesterol, reverse cholesterol transport or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, comprising
- a) providing a screening assay having SCD1 biological activity;
- b) contacting said screening assay with a test compound;
- and
- c) subsequently measuring said biological activity;
- wherein a test compound which modulates said biological activity is said therapeutic agent, or an analog thereof.
A screening assay for identifying compounds useful in human for the treatment of a disorder or condition relating to serum levels of HDL, LDL, total cholesterol, reverse cholesterol transport or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, said screening assay comprising
- a) a screening assay having SCD1 biological activity;
- wherein a test compound which modulates said SCD1 biological activity in said screening assay is a compound, or an analog thereof, which is useful for said treatment.
A method for identifying, from a library of test compounds, a therapeutic agent which is useful in humans for the treatment of a disorder or condition relating to serum levels of HDL, LDL, total cholesterol, reverse cholesterol transport or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, comprising
- a) an assay having measurable SCD1 biological activity;
- wherein a test compound that modulates SCD1 biological activity upon contact with said assay is said therapeutic agent or an analog thereof.
A cell line containing a recombinant SCD1 protein.
A recombinant cell line comprising the SCD1 promoter nucleic acid sequence of SEQ ID No. 1 operably linked to a reporter gene construct.
An isolated stearoyl-CoA desaturase nucleic acid encoded by the polynucleotide sequence comprising SEQ ID NO. 1.
A reporter gene construct comprising the SCD1 promoter nucleic acid sequence of SEQ ID No. 1 operably linked to a reporter gene.
An isolated stearoyl-CoA desaturase protein.
A method of treating a disease or condition in a human selected from among a disorder or condition relating to serum levels of HDL, LDL, total cholesterol, reverse cholesterol transport or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, said method consisting essentially of inhibition of the activity of SCD1 protein in said human.
A modulator of SCD1 biological activity which is useful in humans for treatment of a disorder or condition relating to serum levels of HDL, LDL, total cholesterol, reverse cholesterol transport or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, identified by a screening assay wherein said modulator detectably modulates SCD1 biological activity.
A composition which is useful in humans for treatment of a disorder or condition relating to serum levels of HDL, LDL, total cholesterol, reverse cholesterol transport or production of secretions from mucous membranes, monounsaturated fatty acids, wax esters, and the like, first identified by a screening assay wherein said composition modulates the biological activity of SCD1.
A process for identifying a SCD1-modulating agent, comprising:
- a) contacting under physiological conditions a chemical agent and a molecule having or inducing SCD1 activity;
- b) detecting a change in the activity of said molecule having or inducing SCD1 activity following said contacting;
- thereby identifying an SCD1 modulating agent.
89 A recombinant cell line comprising a recombinant SCD1 protein.
A recombinant cell line comprising the SCD1 promoter nucleic acid sequence of SEQ ID No. 1 operably linked to a reporter gene construct.
An isolated stearoyl-CoA desaturase encoded by the polynucleotide sequence comprising SEQ ID No. [SCD1 cDNA]
A reporter gene construct comprising the SCD1 promoter nucleic acid sequence of SEQ ID No. 1 operably linked to a reporter gene.
An isolated polypeptide having stearoyl-CoA reductase activity.
A process for treating a human afflicted with a disease or condition relating to serum levels of triglyceride or VLDL comprising inhibiting SCD1 activity in said human.
A modulator of SCD1 activity which is useful in humans for treatment of a disorder or condition relating to serum levels of triglyceride or VLDL wherein said activity was first identified by its ability to modulate SCD1 activity.
A process for identifying a vertebrate delta-9 stearoyl-CoA desaturase-modulating agent, comprising:
- a) contacting under physiological conditions a chemical agent and a molecule having or inducing vertebrate delta-9 stearoyl-CoA desaturase activity;
- b) detecting a change in the activity of said molecule having or inducing vertebrate delta-9 stearoyl-CoA desaturase activity following said contacting;
- thereby identifying a vertebrate delta-9 stearoyl-CoA desaturase modulating agent.
A process for identifying, from a library of test compounds, a therapeutic agent which is useful in humans for the treatment of a disorder or condition relating to serum levels of triglyceride or very low density lipoprotein (VLDL) comprising
- a) providing a screening assay having stearoyl-Coenzyme A desaturase type 1 (SCD1) biological activity as a component thereof;
- b) contacting said SCD1 activity with a test compound;
- c) administering to a human a compound found to modulate said activity in (b);
- and
- (d) detecting a change in serum level of triglyceride or VLDL in said human following said administering;
- thereby identifying an agent useful in the treatment of a disorder or condition relating to serum levels of triglyceride or very low density lipoprotein (VLDL).
115 The process of claim 111 further comprising the step of assaying said therapeutic agent to further select compounds which do not substantially inhibit in a human the activity of delta-5 desaturase, delta-6 desaturase or fatty acid synthetase.
Dependencies are inferred from the claim text.