Genetically encoded protein synthesis inhibitor
Inventors
SCHUMAN, Erin M. • HEUMÜLLER, Maximilian • GLOCK, Caspar
Assignees
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Publication Number
US-12570703-B2
Publication Date
2026-03-10
Expiration Date
Abstract
The present invention relates to an expression system for a genetically encoded protein synthesis inhibitor containing RNA N-glycosidase activity split into two components. The expression system can be combined with genetic targeting systems to achieve cell- and/or tissue-type-specific and/or temporally-specific control of protein synthesis in a host, particularly in a mammalian host.
Core Innovation
The invention relates to a genetically encoded protein synthesis inhibitor having RNA N-glycosidase activity that is implemented as a split ribosome-inactivating protein complex. An atypical class 3 (atypical class 1) ribosome-inactivating protein from maize is split into separately expressed first and second components that together form a complex with RNA N-glycosidase activity, while the first component alone and the second component alone lack RNA N-glycosidase activity.
The described expression system provides reversible, temporal control of protein synthesis inhibition by using inducible expression control responsive to an external stimulus. Expression of the first component and the second component is placed under expression control sequences responsive to an external stimulus external to the expression system or host, and the system additionally includes a trans-acting activator for the expression control sequences.
The trans-acting activator is controlled by a cell- and/or tissue-type specific expression control sequence, enabling targeted cell and/or tissue expression. The document further describes that separate chain expression yields cell type- and temporally controlled inhibition with recovery of protein synthesis, and presents kit, host, and method embodiments for research, drug screening, and medicine.
Claims Coverage
Two independent claims are identified: an expression system claim and a kit claim. Across these independent claims, the inventive subject matter is organized around splitting a genetically encoded protein synthesis inhibitor into two separately expressed inactive components that reconstitute an RNA N-glycosidase-active complex, combined with external-stimulus inducible expression for reversible, temporal inhibition and cell- and/or tissue-specific restriction via a trans-acting activator.
Split inhibitor components that reconstitute RNA N-glycosidase activity
A first nucleic acid sequence encoding a first component and a second nucleic acid sequence encoding a second component, where the first component and the second component together form a complex having RNA N-glycosidase activity, and wherein the first component alone and the second component alone lack RNA N-glycosidase activity.
Inducible expression control responsive to external stimulus for reversible temporal inhibition
The first expression control sequence or the second expression control sequence comprises an inducible expression control sequence responsive to an external stimulus, wherein the external stimulus is external to the expression system, thereby providing reversible inhibition of protein synthesis and temporal control.
Cell- and/or tissue-type specific trans-acting activator restricting component expression
A third nucleic acid sequence encoding a trans-acting activator for the first and second expression control sequences in operative linkage with a third expression control sequence, wherein the third expression control sequence is a cell- and/or tissue-type specific expression control sequence.
Separate provision of component nucleic acids as a kit
A kit comprising the first and second nucleic acid sequences provided for expression separate from each other, each operatively linked with inducible expression control sequences responsive to an external stimulus external to the host, thereby providing the host with reversible inhibition of protein synthesis.
The independent claims collectively cover a split genetically encoded protein synthesis inhibitor system in which two individually inactive components reconstitute an RNA N-glycosidase-active complex, with inducible external-stimulus control to achieve reversible and temporal inhibition and with a trans-acting activator under cell- and/or tissue-specific control to restrict expression to targeted cells or tissues. The kit claim further recites providing the separate nucleic acid component sequences for host expression under external-inducible control.
Stated Advantages
Reversible inhibition of protein synthesis with temporal control.
Targeted restriction of inhibitor component expression to a targeted cell and/or tissue.
Documented Applications
Research applications for controlling protein synthesis using the split genetically encoded protein synthesis inhibitor system.
Drug screening applications using temporal and reversible inhibition of protein synthesis.
Medical applications including cancer and neurological disorders such as Fragile X syndrome.
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