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• W2771778052 abstract "Human serine protease HTRA1 plays an important role in a plethora of physiological processes by recognition and conversion of numerous different substrates. Various studies suggested that HTRA1 is involved in several diseases, such as osteoarthritis, cancer, age-related macular degeneration or Alzheimer disease. The aim of this work was the generation of molecules that modulate HTRA1 activity, which could act as tools for validation of HTRA1 as a potential therapeutic target.An initial approach was the monomerization of multimeric HTRA1 that is composed of trimers as well as higher oligomers of unknown composition to get an easier to handle and more controllable target for evolutionary design of interacting molecules. Accordingly, structural data of the trimer was applied for the design of amino acid replacements that are supposedly important for trimerization, resulting in stable monomeric fractions of HTRA1 catalytic domain.Three different scaffold libraries were screened by yeast surface display towards binding of monomeric HTRA1. The miniprotein McoTI II-based library, which is a trypsin inhibitor from squash plant, delivered a single molecule that bound monomeric HTRA1 with nanomolar affinity, but not native trimeric HTRA1. Similarly, the two molecules isolated from an immunized VHH library, which is the variable domain of a single domain camelid immunoglobulin, also bind only monomeric HTRA1 with nanomolar affinities, but not native trimeric HTRA1.The third library was a vNAR library, which is the variable domain of a single domain shark immunoglobulin that was synthetically randomized in CDR3. Six independent molecules were isolated against monomeric HTRA1 and five of them were shown to bind native trimeric HTRA1 with micromolar affinities. By stepwise affinity maturation of CDR1 and HV2, affinities were improved to double digit nanomolar affinities.Finally, promising vNAR molecules were soluble expressed and evaluated for modulation of HTRA1 activity by activity assays, resulting in three molecules that enhance HTRA1 activity in a range from 150 % to 400 %. Therefore, we successfully generated activators that enhance HTRA1 activity with different strengths that can be used in in vitro and in vivo assays for validation of human HTRA1 as novel therapeutic target." @default.
• W2771778052 created "2017-12-22" @default.
• W2771778052 creator A5022145386 @default.
• W2771778052 date "2017-01-01" @default.
• W2771778052 modified "2023-09-27" @default.
• W2771778052 title "Structure-Based Monomerization of Human Serine Protease HTRA1 towards Evolutive Engineering of Activity Modulators" @default.
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