HRS Splice Variant Compositions for Non-Canonical Activity Modulation

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Solution Overview

Problem

Existing technologies have not fully exploited the therapeutic potential of aminoacyl-tRNA synthetases due to a lack of understanding of their non-canonical biological activities, such as modulation of cytokine production, cell proliferation, apoptosis, angiogenesis, and cell migration, among others.

Innovation Solution

The development of histidyl-tRNA synthetase (HRS) splice variant polypeptides and polynucleotides with specific domains, such as the WHEP domain and anticodon binding domain, which exhibit non-canonical activities, along with fusion proteins, binding agents, and compositions for modulating these activities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If full-length HRS protein is used, then aminoacylation activity is maintained, but non-canonical biological activities are not sufficiently exploited

Engineering Contradiction:

Improvebiological activity rangeVSAvoidprotein structure complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The HRS protein is divided into distinct functional domains (aminoacylation domain, WHEP domain, anticodon binding domain) through alternative splicing. This segmentation allows individual domains or combinations to be expressed as separate polypeptides, enabling selective exploitation of specific biological activities without requiring the full-length complex protein structure.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Specific functional domains (WHEP domain, anticodon binding domain) are extracted from the full-length HRS protein through alternative splicing to create truncated polypeptides. These extracted domains retain non-canonical biological activities while removing unnecessary portions, thus simplifying the protein structure while maintaining desired functional versatility.

Inventive Principle:

Principle #2Taking out (Extraction)

2Adaptability or versatility

If alternative splicing is used to create truncated forms, then non-canonical activities are revealed, but aminoacylation function may be reduced

Engineering Contradiction:

Improvenon-canonical activity expressionVSAvoidaminoacylation function

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The system employs dynamic alternative splicing regulation to control the expression of different HRS polypeptide variants. This allows cells to dynamically adjust the balance between full-length HRS (maintaining aminoacylation) and truncated variants (providing non-canonical activities) based on physiological conditions, thus maintaining reliability while enabling versatility.

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

Alternative splicing changes the structural parameters of HRS by including or excluding specific exons, thereby creating polypeptides with different domain compositions. This parameter change allows the same gene to produce variants with varying aminoacylation and non-canonical activities, enabling flexible functional adaptation without compromising overall system reliability.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If domain-specific polypeptides are expressed, then specific non-canonical activities are enhanced, but overall protein stability may decrease

Engineering Contradiction:

Improvespecific activity levelVSAvoidpolypeptide stability

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

Domain-specific polypeptides are merged with stability-enhancing elements or expressed in combination with full-length HRS protein. This merging approach allows the truncated variants to achieve high specific non-canonical activities while the full-length protein or stability domains provide structural support, thus resolving the contradiction between activity enhancement and stability maintenance.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS12497466B2Compositions and methods comprising histidyl-tRNA synthetase splice variants having non-canonical biological activities

Publication Date: 2025.12.16 ATYR PHARM INC

AI summary

Isolated histidyl-tRNA synthetase splice variant polynucleotides and polypeptides having non-canonical biological activities are provided, as well as compositions and methods related thereto.