FimH Lectin Domain Mutations for Low-Affinity Mannose Locking
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Solution Overview
Problem
Current vaccines based on wild-type FimH fail to induce highly inhibitory antibodies against E. coli infections, particularly for conditions like urinary tract infections (UTI), as they do not effectively maintain a conformation with low affinity for mannose, which is crucial for blocking bacterial adhesion.
Innovation Solution
Development of FimH lectin domain polypeptides with specific amino acid mutations, such as F71Y and/or F144V, that lock the protein in a low-affinity conformation for mannose, preventing it from switching to a high-affinity state, thereby inducing potent inhibitory antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type FimH is used in vaccines, then the vaccine structure is simple and easy to produce, but it fails to induce highly inhibitory antibodies because it does not maintain a stable low-affinity conformation for mannose
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (F71Y and/or F144V) at positions 71 and 144 of the FimH lectin domain. These mutations alter the conformational equilibrium of the protein, locking it in a low-affinity state for mannose. This parameter change in the protein structure enables the vaccine to induce highly inhibitory antibodies that effectively block bacterial adhesion, resolving the contradiction between vaccine simplicity and immunogenic effectiveness.
2Reliability
If FimH is mutated to lock in low-affinity conformation, then antibody-mediated inhibition of adhesion is enhanced, but the manufacturing process becomes more complex
Solution Approach 1:
The patent introduces specific amino acid substitutions (F71Y and/or F144V) that fundamentally alter the conformational dynamics of FimH. These parameter changes lock the protein in a low-affinity conformation that effectively induces inhibitory antibodies. Despite the genetic modification complexity, the manufacturing process remains relatively straightforward using standard recombinant expression systems, thus resolving the contradiction between enhanced adhesion inhibition and ease of manufacture.
3Ease of operation
If wild-type FimH is used, then the vaccine is easy to administer and produce, but it allows E. coli to switch to high-affinity conformation under mechanical forces of urine excretion
Solution Approach 1:
The patent applies parameter changes through specific mutations (F71Y and/or F144V) that alter the conformational stability parameters of FimH. These mutations create a locked low-affinity state that resists switching to high-affinity conformation under mechanical stress from urine excretion. The vaccine maintains its structural parameter changes in vivo, ensuring stable inhibition of bacterial adhesion while remaining easy to administer, thus resolving the contradiction between ease of operation and conformational stability.
Data Source
AI summary
Polypeptides comprising a FimH lectin domain comprising at least one an amino acid mutation that causes the FimH lectin domain to be in the low affinity conformation for mannose are described. Pharmaceutical compositions which comprise such polypeptides and methods of stimulating an immune response in a subject in need thereof by administration of the polypeptide are further described.