α-Factor Prepro Sequences for Higher Polypeptide Secretion
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Solution Overview
Problem
Existing methods for protein secretion from living cells, particularly in biomanufacturing and mRNA vaccines, face challenges in achieving high levels of polypeptide secretion, leading to increased costs and patient discomfort due to the need for large doses of therapeutic polypeptides.
Innovation Solution
Incorporating α-factor prepro sequences operably linked to payload polypeptides, along with engineered Arabidopsis Root Growth Factor (GLV) secretion peptide sequences, to enhance polypeptide secretion from mammalian and plant cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional protein secretion methods are used, then production costs increase and patient discomfort increases, but polypeptide secretion levels remain insufficient
Solution Approach 1:
The patent modifies the secretion signal sequence parameters by using α-factor prepro sequence instead of conventional signal peptides. This parameter change in the molecular structure of the secretion signal enables dramatically improved polypeptide secretion levels, reducing the amount of polynucleotide required for delivery while maintaining therapeutic efficacy.
Solution Approach 2:
The α-factor prepro sequence acts as an intermediary element that mediates between the payload polypeptide and the cellular secretion machinery. This intermediary secretion signal facilitates efficient translocation and secretion of the therapeutic polypeptide, resolving the contradiction between secretion efficiency and polynucleotide dosage.
2Productivity
If large doses of therapeutic polypeptides are administered, then patient comfort decreases, but adequate secretion levels are achieved
Solution Approach 1:
By changing the secretion signal sequence parameter to α-factor prepro, the patent achieves high secretion efficiency with reduced polynucleotide doses. This parameter modification directly addresses the contradiction by enabling adequate therapeutic effect with smaller, more comfortable doses for patients.
3Productivity
If conventional signal peptides are used, then secretion levels are limited, but sequence complexity remains low
Solution Approach 1:
The α-factor prepro sequence serves as an intermediary secretion signal that bridges the gap between simple conventional signal peptides and the requirement for high secretion levels. Although it adds some sequence complexity, it dramatically improves secretion efficiency, making the trade-off worthwhile for achieving therapeutic goals.
Data Source
AI summary
Disclosed herein is an engineered polypeptide comprising (i) a payload polypeptide, and (ii) a wild-type or engineered α-factor prepro sequence, where the wild-type or engineered α-factor prepro sequence is operably linked to the payload polypeptide. Also provided herein are polynucleotides encoding an engineered polypeptide of the present disclosure, as well as compositions comprising such polynucleotides or engineered polypeptides of the present disclosure. Methods of making and using the disclosed polypeptides, polynucleotides and compositions are also provided.