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Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors.

Publication ,  Journal Article
Koh, CY; Shih, N; Yip, CYC; Li, AWL; Chen, W; Amran, FS; Leong, EJE; Iyer, JK; Croft, G; Mazlan, MIB; Chee, Y-L; Yap, E-S; Monroe, DM ...
Published in: Nature communications
November 2021

Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.

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Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

November 2021

Volume

12

Issue

1

Start / End Page

6912

Related Subject Headings

  • Transcriptome
  • Ticks
  • Thrombosis
  • Thrombin
  • Swine
  • Recombinant Proteins
  • Rats, Sprague-Dawley
  • Rats
  • Proteomics
  • Percutaneous Coronary Intervention
 

Citation

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ICMJE
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Koh, C. Y., Shih, N., Yip, C. Y. C., Li, A. W. L., Chen, W., Amran, F. S., … Chan, M. Y. (2021). Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors. Nature Communications, 12(1), 6912. https://doi.org/10.1038/s41467-021-27275-8
Koh, Cho Yeow, Norrapat Shih, Christina Y. C. Yip, Aaron Wei Liang Li, Weiming Chen, Fathiah S. Amran, Esther Jia En Leong, et al. “Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors.Nature Communications 12, no. 1 (November 2021): 6912. https://doi.org/10.1038/s41467-021-27275-8.
Koh CY, Shih N, Yip CYC, Li AWL, Chen W, Amran FS, et al. Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors. Nature communications. 2021 Nov;12(1):6912.
Koh, Cho Yeow, et al. “Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors.Nature Communications, vol. 12, no. 1, Nov. 2021, p. 6912. Epmc, doi:10.1038/s41467-021-27275-8.
Koh CY, Shih N, Yip CYC, Li AWL, Chen W, Amran FS, Leong EJE, Iyer JK, Croft G, Mazlan MIB, Chee Y-L, Yap E-S, Monroe DM, Hoffman M, Becker RC, de Kleijn DPV, Verma V, Gupta A, Chaudhary VK, Richards AM, Kini RM, Chan MY. Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors. Nature communications. 2021 Nov;12(1):6912.

Published In

Nature communications

DOI

EISSN

2041-1723

ISSN

2041-1723

Publication Date

November 2021

Volume

12

Issue

1

Start / End Page

6912

Related Subject Headings

  • Transcriptome
  • Ticks
  • Thrombosis
  • Thrombin
  • Swine
  • Recombinant Proteins
  • Rats, Sprague-Dawley
  • Rats
  • Proteomics
  • Percutaneous Coronary Intervention