Thiourea Trehalose Mincle Agonists With Lower Reactogenicity
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Solution Overview
Problem
Current Mincle agonists, such as trehalose dimycolate, are too reactogenic and difficult to synthesize, limiting their use in human vaccine applications, while existing carbohydrate derivatives with thiourea or urea groups lack evidence of Mincle agonism.
Innovation Solution
Development of immunomodulatory thiourea and urea carbohydrate compounds that act as Mincle receptor agonists, inducing a Th1/Th17 immune response for vaccines targeting pathogens and autoimmune diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If trehalose dimycolate (TDM) is used as a Mincle agonist, then immunostimulating effect is achieved, but toxicity and reactogenicity increase significantly
Solution Approach 1:
The patent modifies the chemical structure of trehalose dimycolate by changing the fatty acid chain lengths and saturation levels. Specifically, it uses shorter chain lengths (C16-C18) and controlled degrees of saturation to reduce toxicity while preserving Mincle agonist activity. This parameter optimization allows the compound to maintain immunostimulating effects without the excessive reactogenicity of natural TDM.
Solution Approach 2:
The invention introduces specific structural features at particular positions of the molecule - namely the thiourea group at the C6 position of the trehalose backbone. This localized chemical modification creates a specific binding interface that enhances Mincle activation while the rest of the molecule maintains favorable pharmacokinetic properties. The local introduction of the thiourea motif allows selective enhancement of biological activity without compromising overall safety profile.
2Reliability
If trehalose dimycolate is used as a Mincle agonist, then immunostimulating effect is achieved, but synthesis complexity increases
Solution Approach 1:
The patent divides the synthesis process into modular steps: first synthesizing the core trehalose backbone with protected hydroxyl groups, then introducing the thiourea group at C6, and finally deprotecting and adjusting the fatty acid ester groups. This segmentation allows each step to be optimized independently and enables parallel synthesis of different analogs by varying only the fatty acid components in later steps.
Solution Approach 2:
The invention creates a universal synthetic platform where the core trehalose-thiourea structure serves as a common intermediate. Different fatty acid esters can be introduced through standardized esterification reactions, allowing a single synthetic route to generate multiple analogs with different biological activities. This multi-functional platform reduces the overall synthetic complexity compared to synthesizing each analog from scratch.
3Ease of manufacture
If conventional carbohydrate derivatives with thiourea or urea groups are used, then structural properties can be investigated, but Mincle agonist activity is not demonstrated
Solution Approach 1:
The patent uses the thiourea group as a structural intermediary that serves dual purposes: it provides the necessary binding interface for Mincle activation while also serving as a handle for further chemical modification and structural analysis. The thiourea moiety acts as a mediator between the trehalose backbone and the biological target, enabling both biological activity and structural investigation simultaneously.
Solution Approach 2:
The invention creates composite molecular structures combining the trehalose carbohydrate framework with the thiourea functional group. This composite structure integrates the beneficial properties of both components: the stable, well-characterized trehalose core provides structural rigidity and recognition elements, while the flexible thiourea group provides binding capability and chemical modifiability. The composite nature allows systematic variation of either component to optimize both structure and function.
Data Source
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AI summary
The present invention relates to new immunomodulatory thiourea and urea carbohydrate compounds of formula I, pharmaceutical compositions comprising them and the use thereof, mainly as vaccine adjuvants, in the modulation of immune response in a subject, in the treatment and/or prophylaxis of infectious diseases and in the treatment of cancer.