MG53 Mutants Eliminate Metabolic Side Effects
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Solution Overview
Problem
Wild-type MG53 elicits cell membrane repair and cardioprotective functions but also causes deleterious side effects like insulin resistance and metabolic diseases due to its E3 ubiquitin ligase activity, which are not effectively addressed by existing technologies.
Innovation Solution
Development of MG53 mutants with specific serine mutations in the coiled-coil-SPRY region, such as replacing serine with non-serine or non-threonine amino acids like alanine or cysteine at specific positions, to avoid metabolic side effects while retaining cell membrane repair and cardioprotective functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type MG53 is used to achieve cell membrane repair and cardioprotective functions, then therapeutic efficacy is improved, but metabolic side effects such as insulin resistance and obesity occur due to E3 ubiquitin ligase activity
Solution Approach 1:
The patent extracts and removes the harmful E3 ubiquitin ligase activity from the MG53 protein by introducing point mutations in the Ring domain (specifically H129A, H130A, or H129A/H130A double mutations). These mutations eliminate the ubiquitin ligase function while preserving the membrane repair and cardioprotective functions, thereby separating the beneficial effects from the harmful metabolic side effects
Solution Approach 2:
The patent applies local quality modification by making specific point mutations only in the Ring domain region (residues 129-130) while leaving the rest of the MG53 protein structure unchanged. This localized modification approach preserves the overall protein function for membrane repair while specifically eliminating the harmful ubiquitin ligase activity in the mutated region
2Object-generated harmful factors
If E3 ubiquitin ligase activity is eliminated to avoid metabolic side effects, then insulin resistance and obesity are reduced, but cell membrane repair and cardioprotective functions may be compromised
Solution Approach 1:
The patent converts the potentially harmful loss of ubiquitin ligase activity into a beneficial outcome by demonstrating that the H129A/H130A mutations eliminate metabolic side effects while the protein retains its cardioprotective and membrane repair functions through alternative mechanisms, such as direct interaction with cardiac ion channels and membrane structures
Data Source
AI summary
The present invention relates to an MG53 mutant, wherein the MG53 mutant is identical to the amino acid sequence of a wild-type MG53 except for at least one serine in the coiled-coil-SPRY region of the wild-type MG53, which is deleted and/or mutated into any other non-serine or non-threonine amino acid(s). The present invention also relates to a pharmaceutical composition comprising the MG53 mutant, a nucleic acid encoding the MG53 mutant, a method for preparing the MG53 mutant, use of the MG53 mutant in the manufacture of a medicament for treating heart diseases, diabetic cerebrovascular diseases, diabetic ocular complications, diabetic neuropathy, diabetic foot, kidney diseases, and diseases associated with cellular and/or tissue damage. In particular, the MG53 mutant of the present invention may avoid or reduce metabolic side effects, such as, insulin resistance, obesity, diabetes, hypertension, dyslipidemia, etc., brought by the wild-type MG53, while treating heart diseases, diabetic cerebrovascular diseases, diabetic ocular complications, diabetic neuropathy, diabetic foot, kidney diseases, and diseases associated with cellular and/or tissue damage.