Human therapeutic targets and modulators thereof
Inventors
Biggins, John Baxter • BOWMAN, Brian Roger • Verdine, Gregory L.
Assignees
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Publication Number
US-11749375-B2
Publication Date
2023-09-05
Expiration Date
Abstract
Among other things, the present disclosure provides technologies for efficient and effective identification of ETaGs, for example, from fungi genomes. In some embodiments, provided technologies are particularly useful for identifying mammalian targets of biosynthetic products of fungi. In some embodiments, provided technologies are particularly useful for identifying and/or prioritizing human targets for drug development. In some embodiments, provided technologies are particularly useful for developing modulators for human targets based on biosynthetic products of fungi.
Core Innovation
The invention queries a set of nucleic acid sequences found in a fungal strain and comprising a biosynthetic gene cluster, and identifies within at least one fungal nucleic acid sequence an embedded target gene (ETaG). The ETaG is characterized as not required for or not involved in the biosynthesis of the product of the biosynthetic gene cluster, being within a proximity zone relative to at least one gene in the cluster, homologous to a mammalian nucleic acid sequence, and optionally co-regulated with at least one biosynthetic gene in the cluster.
The invention uses the characterized ETaG to guide functional determination by contacting at least one test compound with a gene product encoded by the embedded target gene and determining whether a level or activity of the gene product is altered when the test compound is present versus absent, or comparable to a reference agent having a known effect. In related aspects, the invention provides computer system functionality to perform the querying and identification steps for ETaG characterization within fungal nucleic acid sequences that comprise biosynthetic gene clusters.
The invention also identifies human homologs of ETaG within a proximity zone relative to at least one biosynthetic gene of a biosynthetic gene cluster and optionally assays an effect of the product produced by enzymes encoded by the biosynthetic gene cluster, or an analog of the product, on the human homolog. Further aspects use a product or analog produced by enzymes encoded by a biosynthetic gene cluster, where an ETaG within the proximity zone is homologous to the human target, or encodes the human target, optionally co-regulated with at least one biosynthetic gene, to identify and/or characterize a modulator of a human target and to modulate the human target.
Claims Coverage
The document provides five independent claims covering ETaG discovery in fungal biosynthetic gene cluster sequences, computational implementation of the discovery, compound-based determination of ETaG gene-product modulation, and human-target identification and modulation using biosynthetic products or analogs. Across the independent claims, the inventive coverage centers on ETaG characterization criteria and on using those criteria to connect fungal gene clusters to human homologs and modulator identification.
Embedded target gene discovery from fungal biosynthetic gene clusters
Querying a set of nucleic acid sequences found in a fungal strain and comprising a biosynthetic gene cluster, and identifying within at least one of the fungal nucleic acid sequences an embedded target gene (ETaG) sequence that is not required for or not involved in the biosynthesis of the product of the biosynthetic gene cluster, is within a proximity zone relative to at least one gene in the cluster, is homologous to a mammalian nucleic acid sequence, and is optionally co-regulated with at least one biosynthetic gene in the cluster.
Computer system for querying and identifying embedded target genes in fungal clusters
A computer system adapted to perform querying of a set of nucleic acid sequences found in a fungal strain and comprising a biosynthetic gene cluster, and to identify within at least one fungal nucleic acid sequence an embedded target gene (ETaG) sequence characterized as not required for or not involved in the biosynthesis of the product of the biosynthetic gene cluster, within a proximity zone relative to at least one gene in the cluster, homologous to a mammalian nucleic acid sequence, and optionally co-regulated with at least one biosynthetic gene in the cluster.
Test-compound based determination of ETaG gene-product level or activity
Contacting at least one test compound with a gene product encoded by an embedded target gene (ETaG) in a fungal nucleic acid sequence, where the ETaG is not required for or not involved in biosynthesis of the biosynthetic gene cluster product, is within a proximity zone relative to at least one biosynthetic gene in the cluster, is homologous to a mammalian nucleic acid sequence, and is optionally co-regulated with at least one biosynthetic gene in the cluster; and determining that a level or activity of the gene product is altered when the test compound is present compared with when it is absent, or that the level or activity is comparable to that observed when a reference agent having a known effect on the level or activity is present.
Human homolog identification of embedded target gene within cluster proximity
Identifying a human homolog of an ETaG that is within a proximity zone relative to at least one biosynthetic gene of a biosynthetic gene cluster, and optionally assaying an effect of the product produced by enzymes encoded by the biosynthetic gene cluster, or an analog of the product, on the human homolog.
Human target modulator identification using biosynthetic cluster products and homologous ETaG
A method for identifying and/or characterizing a modulator of a human target comprising providing a product or an analog thereof produced by the enzymes encoded by a biosynthetic gene cluster, where within a proximity zone relative to at least one gene in the biosynthetic gene cluster exists an ETaG that is homologous to the human target, or a nucleic acid sequence that encodes the human target, and is optionally co-regulated with at least one biosynthetic gene in the cluster.
Modulating a human target using a biosynthetic cluster product and proximity-proximate ETaG
Providing a product or an analog thereof produced by the enzymes encoded by a biosynthetic gene cluster, wherein within a proximity zone relative to at least one biosynthetic gene in the biosynthetic gene cluster exists an ETaG that is homologous to the human target, or a nucleic acid sequence that encodes the human target, and is optionally co-regulated with at least one biosynthetic gene in the cluster.
Overall, the independent claims define a pipeline for identifying embedded target genes within fungal biosynthetic gene clusters based on non-requirement for cluster product biosynthesis, proximity to cluster genes, mammalian or human homology, and optional co-regulation, and then linking those ETaGs to functional outcomes through test-compound level or activity determination and through human homolog identification with optional assaying using cluster-produced products or analogs. Additional independent coverage supports computer-system implementation of the ETaG discovery step.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Identifying and/or characterizing a modulator of a human target.
Modulating a human target.
Identifying a human homolog of an ETaG within a proximity zone relative to at least one biosynthetic gene of a biosynthetic gene cluster, and optionally assaying an effect of the product produced by enzymes encoded by the biosynthetic gene cluster, or an analog of the product, on the human homolog.
Determining whether a level or activity of a gene product encoded by an ETaG is altered in the presence of a test compound compared with absence, or is comparable to a reference agent with a known effect.
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