Methods and compositions for identifying therapeutic compounds
First Claim
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1. A method for identifying a candidate compound as a suitable prodrug, comprising:
- (a) providing a candidate compound having an esterified phosphonate group or an esterified carboxyl group;
(b) contacting the candidate compound with an extract that comprises GS-7340 ester hydrolase to produce one or more metabolite compounds; and
(c) identifying the candidate compound as a suitable prodrug if at least one of the one or more metabolite compounds has a phosphonic acid group instead of the esterified phosphonate group of the candidate compound, or a carboxylic acid group instead of the esterified carboxyl group of the candidate compound.
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Abstract
By the present invention, enzymes responsible for prodrug activation are identified and utilized for the identification of candidate compounds as prodrugs. The present invention includes methods for identifying a candidate compound as a suitable prodrug as well as methods of screening candidate compounds for suitability as therapeutic agents.
20 Citations
26 Claims
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1. A method for identifying a candidate compound as a suitable prodrug, comprising:
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(a) providing a candidate compound having an esterified phosphonate group or an esterified carboxyl group;
(b) contacting the candidate compound with an extract that comprises GS-7340 ester hydrolase to produce one or more metabolite compounds; and
(c) identifying the candidate compound as a suitable prodrug if at least one of the one or more metabolite compounds has a phosphonic acid group instead of the esterified phosphonate group of the candidate compound, or a carboxylic acid group instead of the esterified carboxyl group of the candidate compound. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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10. A method of screening candidate compounds for suitability as therapeutic agents, comprising:
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(a) providing a candidate compound identified by providing the candidate compound having an esterified phosphonate group or an esterified carboxyl group, contacting the candidate compound with an extract that has GS-7340 ester hydrolase activity to produce one or more metabolite compounds, and identifying the candidate compound as a suitable prodrug if at least one of the one or more metabolite compounds has a phosphonic acid group instead of the esterified phosphonate group of the candidate compound, or a carboxylic acid group instead of the esterified carboxyl group of the candidate compound; and
(b) determining the therapeutic activity of the candidate compound; and
(c) determining the intracellular persistence of the candidate compound. - View Dependent Claims (11, 12, 13, 14, 15, 16)
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17. A method for identifying a candidate compound as a suitable prodrug, comprising:
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(a) providing a candidate compound formed by substituting an esterified phosphonate or an esterified carboxyl group into a prototype compound believed to have therapeutic activity;
(b) contacting the candidate compound with an extract of peripheral blood mononuclear cells that has GS-7340 ester hydrolase activity to produce one or more metabolite compounds; and
(c) identifying the candidate compound as a suitable prodrug if at least one of the one or more metabolite compounds has a phosphonic acid group instead of the esterified phosphonate group of the candidate compound, or a carboxylic acid group instead of the esterified carboxyl group of the candidate compound. - View Dependent Claims (18, 19, 20, 21, 22, 23, 24, 25)
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26. A method for identifying a candidate compound as a suitable prodrug, comprising:
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(a) providing a candidate compound having an esterified phosphonate group or an esterified carboxyl group;
(b) contacting the candidate compound with an extract that comprises cathepsin A or a fragment thereof to produce one or more metabolite compounds; and
(c) identifying the candidate compound as a suitable prodrug if at least one of the one or more metabolite compounds has a phosphonic acid group instead of the esterified phosphonate group of the candidate compound, or a carboxylic acid group instead of the esterified carboxyl group of the candidate compound.
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Specification