Exploring Structure−Activity Relationships by Engineering Modified Thrombin Inhibitors from the Flea Xenopsylla cheopis

Abstract Engineering of post-translationally sulfated polypeptides from hematophagous organisms has shown promise for the development of novel anticoagulants with improved therapeutic potential. Here, we describe the development of a high-throughput peptide engineering workflow to facilitate rapid assembly of libraries of modified peptide analogues. Library members were designed from the privileged chimeric anticoagulant sulfo-XC43-Hiru, comprised of a peptide fragment of XC43 (from the rat flea Xenopsylla cheopis) and a sulfopeptide fragment of hirudin (from the medicinal leech, Hirudo medicinalis). Focus was placed on exploring the influence of non-native structural motifs through the incorporation of non-canonical amino acids at a number of strategic sites. The thrombin inhibitory activity and cleavage resistance of each analogue is profiled and provides valuable insight into the relationship between the sequence and biological activity of these molecules.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-11-06
DOI
https://doi.org/10.1021/acs.jmedchem.6c02175
Primary Topic
Chemical Synthesis and Analysis
Type
article
Field-Weighted Citation Impact
0.00

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article

Exploring Structure−Activity Relationships by Engineering Modified Thrombin Inhibitors from the Flea Xenopsylla cheopis

Daniel Ford, Jorge Ripoll‐Rozada, Angus S. Mackay, José A. Manso et al.
Journal of Medicinal Chemistry
Chemical Synthesis and Analysis
article

Exploring Structure−Activity Relationships by Engineering Modified Thrombin Inhibitors from the Flea Xenopsylla cheopis

Daniel Ford, Jorge Ripoll‐Rozada, Angus S. Mackay, José A. Manso, Joshua W. C. Maxwell, Richard J. Payne, Pedro Miguel Martins, Pedro José Barbosa Pereira, K. J. Harrison, Harry P. Aitken
article en

Abstract

Abstract Engineering of post-translationally sulfated polypeptides from hematophagous organisms has shown promise for the development of novel anticoagulants with improved therapeutic potential. Here, we describe the development of a high-throughput peptide engineering workflow to facilitate rapid assembly of libraries of modified peptide analogues. Library members were designed from the privileged chimeric anticoagulant sulfo-XC43-Hiru, comprised of a peptide fragment of XC43 (from the rat flea Xenopsylla cheopis) and a sulfopeptide fragment of hirudin (from the medicinal leech, Hirudo medicinalis). Focus was placed on exploring the influence of non-native structural motifs through the incorporation of non-canonical amino acids at a number of strategic sites. The thrombin inhibitory activity and cleavage resistance of each analogue is profiled and provides valuable insight into the relationship between the sequence and biological activity of these molecules.

Journal of Medicinal Chemistry
The University of Sydney (AU), Universidad de Cantabria (ES), Consejo Superior de Investigaciones Científicas (ES), Universidade do Porto (PT)
Australian Government, Ministerio de Ciencia, Tecnología e Innovación Productiva, NSW Health, Fundação para a Ciência e a Tecnologia, European Regional Development Fund, NextGenerationEU
Openalex Percentile: Top 27%
Chemical Synthesis and Analysis
DOISourceOpenAlex
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