Truncated T3SS Effector Compositions for Chronic Inflammation
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Solution Overview
Problem
There is a need for new and effective methods to treat chronic inflammatory conditions associated with significant morbidity and mortality rates, such as arthritis, cardiovascular diseases, allergies, chronic obstructive pulmonary disease, diabetes, inflammatory bowel disease, and cancer, as existing treatments are inadequate.
Innovation Solution
Compositions comprising two or more truncated T3SS bacterial effector polypeptides, including YopE, YopJ, YopM, NleE, NleC, NleB, OspZ, IpaH4.5, IpaH7.8, and IpaH9.8, formulated with a protein transduction domain, are used to modulate immune responses and treat inflammatory conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for chronic inflammatory conditions, then current standard of care is maintained, but treatment effectiveness is inadequate
Solution Approach 1:
The patent repurposes bacterial effector proteins, which are naturally harmful pathogens that cause disease, into beneficial therapeutic agents. These truncated bacterial effector polypeptides (such as YopE, YopJ, YopM from Yersinia and IpaH4.5, IpaH7.8, IpaH9.8 from Salmonella) that normally harm host cells are now used to treat chronic inflammatory conditions by modulating immune responses and reducing inflammation, effectively converting a harmful factor into a therapeutic benefit
Solution Approach 2:
The patent modifies the bacterial effector proteins by truncating them to specific lengths and domains that optimize their therapeutic function. The full-length bacterial effectors are cut to specific fragments (e.g., YopE amino acids 1-180, YopJ amino acids 1-172) that retain immunomodulatory activity while reducing harmful effects, and these are combined with protein transduction domains to enhance cellular uptake and bioavailability, thereby changing the parameters of the protein structure to achieve therapeutic efficacy
2Reliability
If full-length bacterial effector polypeptides are used, then complete protein function is retained, but pharmacokinetic properties and bioavailability are suboptimal
Solution Approach 1:
The patent divides full-length bacterial effector polypeptides into smaller truncated segments that retain the essential functional domains while improving pharmacokinetic properties. For example, YopE is truncated to amino acids 1-180, YopJ to 1-172, YopM to 1-166, and various IpaH proteins to specific N-terminal or C-terminal fragments. This segmentation improves cellular uptake, reduces immunogenicity, and enhances overall therapeutic performance while maintaining the core immunomodulatory function
Solution Approach 2:
The patent extracts only the essential functional domains from the full-length bacterial effector proteins, removing unnecessary portions that may hinder pharmacokinetic performance. The protein transduction domain (PTD) is extracted and attached to the truncated effectors to enhance cellular penetration. This extraction of critical functional elements while removing non-essential portions optimizes the therapeutic index and bioavailability of the conjugates
Data Source
AI summary
Provided herein are methods and compositions comprising constructs that include two or more truncated T3SS bacterial effector polypeptides. Also provided are pharmaceutical compositions comprising the constructs and methods of treatment of inflammatory disorders based on administering such constructs.