Stabilized Filovirus Glycoprotein Trimers via Amino Acid Substitutions
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Solution Overview
Problem
Current vaccine development for filoviruses, such as Ebola and Marburg, faces challenges in producing stable glycoprotein trimers that effectively induce broadly neutralizing antibodies while minimizing non-neutralizing epitopes, leading to variable vaccine efficacy.
Innovation Solution
The development of recombinant Filovirus glycoproteins with specific amino acid substitutions, particularly at positions 588 and 577, to stabilize trimer formation and improve trimer yields, resembling the native protein configuration, which enhances binding with broadly neutralizing antibodies and reduces non-neutralizing antibody induction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant Filovirus glycoproteins are produced using conventional methods, then vaccine development can proceed, but the glycoprotein trimers are unstable and do not effectively induce broadly neutralizing antibodies
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (K588F, K588W, K588L, K588M, K588I, K588V, K588A, K588Y, K588Q, K588E, K588D, K588H, K588N, K588P, K588G, K588S, K588T, K588C, K588X) at position 588 of the Filovirus glycoprotein sequence. These substitutions change the chemical properties and stability parameters of the glycoprotein, enabling it to maintain a stable pre-fusion trimeric conformation that effectively induces broadly neutralizing antibodies.
2Manufacturing precision
If amino acid substitutions are introduced to stabilize trimer formation, then trimer yield improves, but the complexity of protein production increases
Solution Approach 1:
The patent applies local quality by introducing amino acid substitutions at a specific local position (position 588) in the glycoprotein sequence. This localized modification at a single residue position achieves global stabilization of the trimeric structure without requiring complex modifications throughout the entire protein sequence, thereby improving trimer formation while minimizing production complexity.
3Ease of manufacture
If conventional glycoprotein production methods are used, then production process is simple, but non-neutralizing epitopes are induced which reduce vaccine efficacy
Solution Approach 1:
The patent changes the amino acid parameter at position 588 to stabilize the pre-fusion trimeric conformation of the glycoprotein. This parameter change prevents the protein from adopting post-fusion conformations that would expose non-neutralizing epitopes, thereby eliminating the harmful effect of inducing non-neutralizing antibodies while maintaining a relatively simple production process.
Data Source
AI summary
Filovirus glycoprotein mutations that stabilize the trimeric form of the glycoprotein are provided. The Filovirus glycoproteins have certain amino acid substitutions at specified positions in the glycoprotein sequence. The Filovirus glycoproteins described herein have an improved percentage of trimer formation and/or an improved trimer yield as compared to a Filovirus glycoprotein that does not have one or more of the indicated amino acid substitutions. Also provided are nucleic acid molecules and vectors encoding the Filovirus glycoproteins, as well as compositions containing the Filovirus glycoproteins, nucleic acid, and vectors.