Methods for screening
AssigneeFred Hutchinson Cancer Research Center
InventorsJames OLSON, Christopher MEHLIN, Mark STROUD, Julian SIMON, Colin CORRENTI, Patrick PADDISON, Roland STRONG, Damon MAY
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Abstract
Methods and systems for discovering drug candidates are disclosed. Methods and systems can include generating libraries of potential drug candidates (e.g., libraries of peptides) that can be screened to identify sub-libraries of potential drug candidates (e.g., sub-libraries of peptides) having selected pharmacological properties. Methods of making and using peptide libraries are also provided. D-amino acid chlorotoxins and D-amino acid chlorotoxin variants are also provided.
Claims147
A method for identifying a drug candidate having a pharmacological property, the method comprising:
- analyzing an isolated sample from a subject following administration of a plurality of drug candidates to the subject;
- and
- identifying in the isolated sample at least one drug candidate having the pharmacological property.
A method for identifying drug candidates having a pharmacological property, the method comprising:
- administering, to a subject, a composition comprising a plurality of drug candidates;
- obtaining, from the subject, a sample comprising at least some of the drug candidates in the plurality;
- and
- analyzing the sample to determine the identity of the at least some of the drug candidates having the pharmacological property.
The method of any one of the preceding claims, wherein the pharmacological property comprises oral bioavailability, capability to pass the blood-brain barrier, exclusion by the blood-brain barrier, serum half-life, capability to penetrate cells, capability to enter subcellular organelles or other cellular domains, capability to target organs or tissue, capability to target cancerous tissue, or a combination thereof.
The method of any one of the preceding claims, further comprising screening the at least some of the peptides to identify which peptides exhibit an activity for inhibiting a protein:protein interaction, inhibiting antagonism of a receptor, inhibiting binding of an agonist to a receptor, modulating an ion channel, inhibiting a signaling pathway, activating a signaling pathway, and/or a inhibiting a protein:small molecule interaction.
The method of any one of the preceding claims, further comprising obtaining from the subject a plurality of samples, each sample being obtained at a different time point after administering the plurality of peptides.
The method of any one of the preceding claims, wherein the identity of the at least some of the peptides is determined using mass spectrometry, wherein each of the peptides comprise a unique mass signature or digest fragment mass signature detected by a mass spectrometer.
The method of any one of the preceding claims, wherein the plurality of drug candidates comprises greater than 5 drug candidates, greater than 10 drug candidates, greater than 100 drug candidates, greater than 1000 drug candidates, or greater than 10000 drug candidates.
The method of any one of the preceding claims, wherein at least one peptide of the plurality of peptides comprises a detectable label for tracing the at least one peptide in the subject.
The method of any one of the preceding claims, wherein at least one peptide of the plurality of peptides comprises a hydrophobic moiety conjugated to the N-terminus of the at least one peptide, wherein the at least one peptide exhibits an increased half-life as compared to the at least one peptide lacking the hydrophobic moiety.
The method of any one of the preceding claims, wherein the sample comprises a tissue sample or a fluid sample.
The method of any one of the preceding claims, further comprising using the pharmacological property common to the drug candidates to generate additional drug candidates having the pharmacological property.
The method of any one of the preceding claims, wherein the subject is an animal.
The method of any one of the preceding claims, further comprising establishing a relationship between the structure and the pharmacological property of the drug candidates.
The method of any one of the preceding claims, further comprising obtaining a plurality of samples at a selected time interval for a selected duration of time following administration.
A method of generating a mass-defined drug candidate library, the method comprising:
- producing a plurality of drug candidates, at least some of the drug candidates each having a unique mass signature or digest fragment mass signature;
- analyzing the plurality of drug candidates using mass spectrometry to measure the unique mass signature or digest fragment mass signature for the at least some of drug candidates;
- and
- generating a mass-defined drug candidate library comprising the at least some of the plurality of drug candidates, the drug candidate library being generated based on a pharmacological property, wherein the identity of the drug candidates in the mass-defined drug candidate library can be determined with the unique mass signature or digest fragment mass signature of each of the drug candidates.
A method of determining a distribution profile of knotted-peptides administered to a subject by different administration pathways, the method comprising:
- administering to the subject a light knotted-peptide, the light knotted-peptide being administered by a first route of delivery and having a lower molecular weight than a heavy knotted-peptide having the same sequence as the light knotted-peptide;
- administering to the subject the heavy knotted-peptide, the heavy knotted-peptide being administered by a second route of delivery that is different than the first route of delivery;
- and
- comparing a quantity of the light knotted-peptide to a quantity of the heavy knotted-peptide obtained from a tissue or fluid sample of the subject, thereby determining the distribution profile of the light and heavy knotted-peptides in the subject based on the first and second routes of delivery, respectively.
A method of determining a distribution profile of knotted-peptides administered to a subject by different administration pathways, the method comprising:
- analyzing an isolated sample from a subject following administration to the subject of a composition comprising a light knotted-peptide, the light knotted-peptide being administered by a first route of delivery and having a lower molecular weight than a heavy knotted-peptide having the same sequence as the light knotted-peptide;
- analyzing an isolated sample from a subject following administration to the subject of a composition comprising the heavy knotted-peptide, the heavy knotted-peptide being administered by a second route of delivery that is different than the first route of delivery;
- and
- comparing a quantity of the light knotted-peptide to a quantity of the heavy knotted-peptide obtained from a tissue or fluid sample of the subject, thereby determining the distribution profile of the light and heavy knotted-peptides in the subject based on the first and second routes of delivery, respectively.
A method for identifying drug candidates having a pharmacological property, the method comprising:
- administering, to a subject, a composition comprising a plurality of drug candidates;
- obtaining, from the subject, a sample comprising at least some of the drug candidates in the plurality;
- and
- analyzing the sample to determine the identity of the at least some of the drug candidates having the pharmacological property.
A method of generating mass-defined drug candidate libraries, the method comprising:
- producing a plurality of drug candidates, at least some of the drug candidates each having a unique mass signature or digest fragment mass signature;
- analyzing the plurality of drug candidates using mass spectrometry to measure the unique mass signature or digest fragment mass signature for the at least some of drug candidates;
- and
- generating a mass-defined drug candidate library comprising the at least some of the plurality of drug candidates, the drug candidate library being generated based on a pharmacological property, wherein the identity of the drug candidates in the mass-defined drug candidate library can be determined with the unique mass signature or digest fragment mass signature of each of the drug candidates.
A method of determining a distribution profile of knotted-peptides administered to a subject by different administration pathways, the method comprising:
- administering to the subject a light knotted-peptide, the light knotted-peptide being administered by a first route of delivery and having a lower molecular weight than a heavy knotted-peptide having the same sequence as the light knotted-peptide;
- administering to the subject the heavy knotted-peptide, the heavy knotted-peptide being administered by a second route of delivery that is different than the first route of delivery;
- and
- comparing a quantity of the light knotted-peptide to a quantity of the heavy knotted-peptide obtained from a tissue or fluid sample of the subject, thereby determining the distribution profile of the light and heavy knotted-peptides in the subject based on the first and second routes of delivery, respectively.
A peptide for imaging a tumor in a subject, the peptide comprising a chlorotoxin comprising an amino acid sequence having at least three D-amino acids and the peptide having a secondary structure configured to bind to the tumor, wherein the peptide further comprises a detectable label.
A peptide comprising an amino acid sequence having at least 80% identical to the following sequence of MCMPCFTTDHQMARXCDDCCGGXGRGXCYGPQCLCR, wherein at least three of the amino acids in the amino acid sequence are D-amino acids, wherein X is selected from K, A and R.
The peptide any of claim 130-132 or 135-137, wherein the detectable label is conjugated to the N-terminus of the peptide or conjugated to a lysine residue in the peptide.
Dependencies are inferred from the claim text.