Engineered Peptide Inhibitors for LDHA Activity Control
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Solution Overview
Problem
There is a need for agents that specifically alter the activity of lactate dehydrogenase A (LDHA), a key metabolic enzyme implicated in various disease processes including cancer, diabetes, and Bid-Hogg-Dubé syndrome, as existing technologies have not effectively addressed the inhibition of LDHA activity.
Innovation Solution
The development of peptides with a core sequence differing from SEQ ID NO: 10 by a single amino acid substitution, which exhibit at least 70% sequence identity and inhibit LDHA activity in cells, are used to reduce or inhibit LDHA activity in cells and treat conditions characterized by elevated LDHA levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing technologies are used to inhibit LDHA activity, then the need for specific LDHA inhibitors remains unaddressed, but no effective inhibition is achieved
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence parameters of the FLCN protein to create peptide variants with optimized LDHA inhibition activity. Specifically, the core sequence (amino acids 219-228) is subjected to systematic amino acid substitutions to generate variants with at least 70% sequence identity, where certain substitutions enhance binding affinity and inhibitory potency against LDHA while maintaining structural integrity
Solution Approach 2:
The patent extracts the inhibitory functional domain from the full-length FLCN protein by isolating the 10-amino acid core sequence (residues 219-228) that is responsible for LDHA inhibition. This extracted peptide sequence can be produced independently as a therapeutic agent, allowing for simplified production and targeted delivery to inhibit LDHA activity in diseases such as cancer and BHD syndrome
2Reliability
If peptides with high sequence identity to SEQ ID NO: 10 are used, then LDHA inhibition is achieved, but the need for optimized variants remains
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at particular positions within the core sequence to enhance local binding interactions with LDHA. The patent identifies that certain amino acid positions, when substituted with specific residues, locally improve the peptide's affinity for LDHA and its inhibitory effectiveness, while maintaining the overall structural framework of the original sequence
Solution Approach 2:
The patent applies dynamics by creating a library of peptide variants with different amino acid substitutions that can dynamically adapt to optimize LDHA inhibition. The variants with at least 70% sequence identity to SEQ ID NO: 10 provide a range of inhibitory activities, allowing selection of the most effective variant for specific therapeutic applications while facilitating optimized production protocols
Data Source
AI summary
The present disclosure is directed to one or more engineered peptide inhibitors against the lactate dehydrogenase A (LDHA) activity in cells. The disclosure also provides compositions, and kits including the one or more peptide inhibitors, and methods of using the one or more peptide inhibitors. The peptide inhibitors and compositions can be used for treatment of conditions in which there is abnormally high LDHA activity, such as cancer or metabolic diseases, infectious diseases, mendelian disorders, inflammatory diseases, neurodegenerative and neuropathological diseases, neuropsychological disorders, obesity and eating disorders, chronic diseases and genetic diseases.