Alpha Synuclein Picobody Truncation for Blood-Brain Barrier Crossing

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Solution Overview

Problem

Current diagnostic and therapeutic approaches for synucleinopathies, such as Parkinson's Disease and dementia with Lewy bodies, face challenges in effectively targeting and inhibiting alpha synuclein aggregation due to limitations in crossing the brain-blood barrier and specificity.

Innovation Solution

Development of picobodies, which are truncated nanobodies with an N-terminal truncation of 8 residues, allowing for enhanced bioavailability and specific binding to alpha synuclein, inhibiting its aggregation and potentially improving diagnostic and therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antibodies are used to target alpha synuclein, then they have high binding affinity, but they cannot effectively cross the brain-blood barrier due to their large molecular weight

Engineering Contradiction:

Improvebinding affinityVSAvoidmolecular weight

Core Design Contradiction:

ReliabilityVSWeight of moving object

Solution Approach 1:

The patent segments the conventional antibody structure into a smaller nanobody format (single variable domain instead of full antibody), reducing molecular weight from 150-160 kDa to 12-15 kDa while preserving the essential binding function through retained CDR regions

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent extracts only the essential binding domain (variable region) from the full antibody structure to create nanobodies, and further truncates the N-terminal region to create picobodies, achieving minimal size while maintaining target specificity

Inventive Principle:

Principle #2Taking out (Extraction)

2Ease of operation

If nanobodies are truncated to create picobodies, then bioavailability and brain-blood barrier crossing improve, but structural stability may be compromised

Engineering Contradiction:

ImprovebioavailabilityVSAvoidstructural stability

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The patent applies local quality by selectively truncating only the N-terminal region (8 residues) while preserving the C-terminal region containing the CDR3 loop, which is critical for binding stability and alpha synuclein recognition

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the structural parameters by removing 8 N-terminal amino acid residues to create picobodies, optimizing the balance between size for bioavailability and structural integrity for stability

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If conventional antibodies are used, then they provide comprehensive binding coverage, but they lack specificity for certain alpha synuclein conformations

Engineering Contradiction:

Improvebinding coverageVSAvoidspecificity

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The patent uses short peptides (12-20 residues) as immunogens to generate nanobodies and picobodies that target specific conformational epitopes on alpha synuclein, achieving high specificity for pathological conformations rather than comprehensive binding

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Data Source

PatentUS20240052022A1Engineered picobody to alpha synuclein

Publication Date: 2024.02.15 HAMAD BIN KHALIFA UNIVERSITY

AI summary

Alpha synuclein picobodies, which are N-terminal truncations of alpha synuclein nanobodies are provided. Methods of using alpha synuclein picobodies for diagnosing and treating synucleinopathies are also provided.