Aldolase-TRAP Complex Inhibitors for Malaria Treatment
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Solution Overview
Problem
Current malaria treatments are limited by side effects, high costs, and growing parasite resistance, with a lack of effective targets for drug development, particularly for the glideosome, which is crucial for parasite motility and invasion.
Innovation Solution
Development of compounds that bind to specific residues of Aldolase and TRAP, stabilizing their complex to inhibit glideosome function, thereby disrupting parasite motility and invasion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current malaria treatments are used, then parasite infection can be treated, but side effects and parasite resistance increase
Solution Approach 1:
The patent extracts and targets a specific functional complex (Aldolase-TRAP-glideosome) that is essential for parasite survival but absent in human cells. By isolating this parasite-specific target, the invention enables selective inhibition of the parasite without affecting human cellular processes, thereby reducing side effects and avoiding cross-resistance with existing treatments.
Solution Approach 2:
The patent employs structure-based drug design to create compounds with specific local interactions at the Aldolase-TRAP interface. The small molecules are designed to bind at particular residues and stabilize specific conformations of the complex, providing localized, precise inhibition of glideosome function while leaving other parasite functions intact.
2Reliability
If new drug targets are developed, then resistance can be reduced, but development time and cost increase
Solution Approach 1:
The patent performs preliminary structural characterization of the Aldolase-TRAP complex interface before compound optimization. By using NMR spectroscopy and structure-based design in early stages to identify key binding residues and interaction patterns, the invention accelerates subsequent compound development and reduces the overall drug discovery timeline.
Solution Approach 2:
The patent systematically varies molecular parameters of candidate compounds to optimize binding affinity and selectivity at the Aldolase-TRAP interface. By changing structural parameters such as molecular size, functional groups, and binding conformation, the invention rapidly generates optimized leads with improved potency and resistance profiles.
Data Source
AI summary
In one aspect, the present invention relates to a method of identifying compounds useful in modifying the activity of Aldolase. The method includes providing a first model comprising Aldolase or residues of the amino acid sequence corresponding to SEQ ID NO: 1 said residues being at amino acid positions selected from the group consisting of 10-13, 26, 27, 29, 30, 31, 32, 33, 37, 39, 40, 41, 43, 44, 47, 48, 51, 52, 60, 63, 66, 79, 84, 85, 92, 93, 103, 106-109, 112-117, 138, 142, 146, 148, 151, 153, 179, 182, 183, 185, 186, 194, 196, 197, 198, 199, 208, 226-228, 231-269, 270, 272, 277-283, 285-289, 294, 295, 297-299, 301-304, 306-310, 312, 313, 316, 317, 319, 321, 323, 326, 330, 344, 345, and 347, providing one or more candidate compounds, evaluating contact between the candidate compounds and the first model to determine which of the one or more candidate compounds have an ability to bind to and/or fit in the first model, and identifying compounds which, based on said evaluating, have the ability to bind to and/or fit in the first model as compounds potentially useful for modifying the activity of Aldolase. The present invention also discloses compounds and compositions which modify the activity of Aldolase, or a complex between Aldolase and TRAP. Methods of treating or preventing malaria, or an infection by apicomplexan organisms are also disclosed.