Evidence map›Paper›PMID 40075385›Full record

ArticleBMC biotechnology2025

Enhancement of plasma kallikrein specificity of antitrypsin variants identified by phage display and partial reversion.

Sangavi Sivananthan, Tyler Seto, Negin C Tehrani, Varsha Bhakta, William P Sheffield

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Article in BMC biotechnology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

5 authors.

Sangavi SivananthanDepartment of Pathology and Molecular Medicine HSC 4H19, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
Tyler SetoDepartment of Pathology and Molecular Medicine HSC 4H19, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
Negin C TehraniDepartment of Pathology and Molecular Medicine HSC 4H19, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
Varsha BhaktaDepartment of Pathology and Molecular Medicine HSC 4H19, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
William P SheffieldDepartment of Pathology and Molecular Medicine HSC 4H19, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada. sheffiel@mcmaster.ca.

Funding

Canadian Blood Services DRG2023-WS
6 · The paper itself

Abstract

backgroundThe naturally occurring variant Alpha-1 Antitrypsin M358R (AAT M358R), modified at the P1 position of the reactive center loop (RCL), shifts its inhibitory protease target from neutrophil elastase to multiple coagulation and contact proteases, including activated plasma kallikrein (Pka; KLKB1). Our aim was to increase the specificity of AAT M358R for Pka as a potential novel therapeutic agent to treat pathological swelling arising from elevated Pka levels in patients with Hereditary Angioedema.

resultsTwo AAT M358R T7Select phage display libraries randomized at RCL positions P7-P3 and P2-P3' were iteratively probed with Pka. The most abundant Pka-inhibitory motifs from phage display were P7-P3, QLIPS; and P2-P3', VRRAY (mutated residues in bold). AAT variants expressing these motifs, alone or in combination, as well as six less-mutated P7-P3 revertant proteins were expressed, purified, and characterized kinetically. Variants AAT M358R (QLIPS) (designated 7-QLIPS-3) and 7-FLEPS-3 exhibited significantly enhanced selectivity for Pka (over factor XIa) by factors of 6.9 and 9.2, respectively, without increasing the stoichiometry of inhibition (SI) or decreasing the inhibition rate relative to AAT M358R. No other variants matched this profile.

conclusionsPro substitution at P4 was found to be important for enhanced inhibition of Pka by AAT M358R. Two novel variants with this substitution are more rapid and selective inhibitors of Pka than AAT M358R and may provide better control of Pka in vivo than existing HAE therapeutics.

Indexed as

alpha 1-AntitrypsinPlasma KallikreinCell Surface Display TechniquesHumansPeptide LibrarySubstrate Specificityalpha 1-AntitrypsinPeptide LibraryPlasma KallikreinAlpha-1 antitrypsinHereditary angioedemaMutagenesisPhage displayPlasma kallikreinReactive centre loop

Identifiers

PMID40075385
PMCPMC11905551

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