Oligomeric Compound Assay for Undruggable Target Uptake
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Solution Overview
Problem
Traditional small molecule technologies struggle with 'undruggable' molecular targets due to structural similarities, unknown biological functions, and difficulties in drug screening assays, while antisense drugs can differentiate based on genetic sequence, but face challenges with cellular uptake and efficacy.
Innovation Solution
The method involves using reporter and competitor oligomeric compounds to assess cellular uptake and optimize antisense activity by varying concentrations in test samples, employing specific cell types like hepatocytes, and potentially using excipients to saturate unproductive accumulation mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional small molecule technology is used to target molecular targets, then drug development is straightforward with small molecules, but many molecular targets are considered 'undruggable' due to structural similarities, unknown biological functions, and difficulties in drug screening assays
Solution Approach 1:
The patent introduces reporter oligomeric compounds and competitor oligomeric compounds as intermediary tools to enable drug screening for undruggable targets. These intermediary compounds facilitate the detection and assessment of antisense drug activity against targets that cannot be directly screened with traditional small molecule methods, thereby resolving the contradiction between target accessibility and screening reliability
2Measurement precision
If antisense drugs are used to discriminate between targets based on genetic sequence, then specificity for undruggable targets is improved, but cellular uptake and efficacy are compromised
Solution Approach 1:
The patent employs parameter changes by systematically varying the concentration of competitor oligomeric compounds in competition assays to assess and optimize cellular uptake of antisense drugs. By adjusting this parameter and measuring its effect on reporter oligomeric compound uptake, the patent identifies optimal conditions that maintain both target discrimination accuracy and cellular uptake efficiency
3Reliability
If competition assays are performed with varying concentrations of reporter and competitor oligomeric compounds to assess cellular uptake, then uptake optimization is achieved, but assay complexity increases
Solution Approach 1:
The patent creates a universal competition assay platform that can assess cellular uptake of various antisense drugs against different undruggable targets using the same methodology. The assay uses a standardized system with reporter and competitor oligomeric compounds that can be applied across multiple drug candidates and target types, reducing the need for separate complex assays for each drug-target pair and thereby managing complexity while maintaining assessment accuracy
Data Source
AI summary
The present invention provides method of optimizing the efficacy and potency of antisense drugs. In certain embodiments, the invention provides assays useful for determining favorable oligonucleotide characteristics and excipients for improved cellular uptake.