PMID- 34824278
OWN - NLM
STAT- MEDLINE
DCOM- 20220103
LR  - 20230208
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 12
IP  - 1
DP  - 2021 Nov 25
TI  - Efficacy and safety of next-generation tick transcriptome-derived direct thrombin 
      inhibitors.
PG  - 6912
LID - 10.1038/s41467-021-27275-8 [doi]
LID - 6912
AB  - 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 K(i) 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 naive 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.
CI  - (c) 2021. The Author(s).
FAU - Koh, Cho Yeow
AU  - Koh CY
AUID- ORCID: 0000-0003-0002-4603
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Shih, Norrapat
AU  - Shih N
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Yip, Christina Y C
AU  - Yip CYC
AD  - Department of Laboratory Medicine, National University Hospital, Singapore, 
      Singapore.
FAU - Li, Aaron Wei Liang
AU  - Li AWL
AUID- ORCID: 0000-0002-7587-1420
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Chen, Weiming
AU  - Chen W
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Amran, Fathiah S
AU  - Amran FS
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Leong, Esther Jia En
AU  - Leong EJE
AD  - Department of Biological Sciences, National University of Singapore, Singapore, 
      Singapore.
FAU - Iyer, Janaki Krishnamoorthy
AU  - Iyer JK
AD  - Department of Biological Sciences, National University of Singapore, Singapore, 
      Singapore.
FAU - Croft, Grace
AU  - Croft G
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Mazlan, Muhammad Ibrahim Bin
AU  - Mazlan MIB
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
FAU - Chee, Yen-Lin
AU  - Chee YL
AD  - Department of Haematology, National Cancer Institute, Singapore, Singapore.
FAU - Yap, Eng-Soo
AU  - Yap ES
AD  - Department of Haematology, National Cancer Institute, Singapore, Singapore.
FAU - Monroe, Dougald M
AU  - Monroe DM
AD  - Division of Hematology/Oncology, University of North Carolina at Chapel Hill, 
      Chapel Hill, NC, USA.
FAU - Hoffman, Maureane
AU  - Hoffman M
AUID- ORCID: 0000-0001-7123-0100
AD  - Department of Pathology, Duke University, Durham, NC, USA.
FAU - Becker, Richard C
AU  - Becker RC
AD  - University of Cincinnati, Cincinnati, OH, USA.
FAU - de Kleijn, Dominique P V
AU  - de Kleijn DPV
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore.
AD  - Department of Vascular Surgery, University Medical Center Utrecht & Netherlands 
      heart Institute, Utrecht, The Netherlands.
FAU - Verma, Vaishali
AU  - Verma V
AUID- ORCID: 0000-0001-5076-7435
AD  - Centre for Innovation in Infectious Disease Research, Education, and Training 
      (CIIDRET), University of Delhi South Campus, New Delhi, India.
FAU - Gupta, Amita
AU  - Gupta A
AD  - Centre for Innovation in Infectious Disease Research, Education, and Training 
      (CIIDRET), University of Delhi South Campus, New Delhi, India.
FAU - Chaudhary, Vijay K
AU  - Chaudhary VK
AD  - Centre for Innovation in Infectious Disease Research, Education, and Training 
      (CIIDRET), University of Delhi South Campus, New Delhi, India.
FAU - Richards, A Mark
AU  - Richards AM
AD  - Cardiovascular Research Institute, NUHS, Singapore, Singapore.
AD  - Christchurch Heart Institute, University of Otago, Otago, New Zealand.
FAU - Kini, R Manjunatha
AU  - Kini RM
AUID- ORCID: 0000-0002-6100-3251
AD  - Department of Biological Sciences, National University of Singapore, Singapore, 
      Singapore. dbskinim@nus.edu.sg.
AD  - Department of Pharmacology, Yong Loo-Lin School of Medicine, National University 
      of Singapore, Singapore, Singapore. dbskinim@nus.edu.sg.
FAU - Chan, Mark Y
AU  - Chan MY
AUID- ORCID: 0000-0003-0389-7450
AD  - Department of Medicine, Yong Loo Lin School of Medicine, National University of 
      Singapore, Singapore, Singapore. mark_chan@nuhs.edu.sg.
AD  - Cardiac Department, National University Heart Centre, Singapore, Singapore. 
      mark_chan@nuhs.edu.sg.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211125
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Antibodies)
RN  - 0 (Anticoagulants)
RN  - 0 (Antidotes)
RN  - 0 (Antithrombins)
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Hirudins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Recombinant Proteins)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.4.21.5 (Thrombin)
RN  - R16CO5Y76E (Aspirin)
RN  - TN9BEX005G (bivalirudin)
SB  - IM
MH  - Amblyomma
MH  - Animals
MH  - Antibodies
MH  - Anticoagulants
MH  - Antidotes
MH  - Antithrombins/*pharmacology
MH  - Aspirin
MH  - Drug Development
MH  - Drug Discovery
MH  - Female
MH  - Fibrinolytic Agents/*pharmacology
MH  - Gene Library
MH  - Heparin
MH  - Hirudins
MH  - Humans
MH  - Male
MH  - Peptide Fragments
MH  - Percutaneous Coronary Intervention/methods
MH  - Proteomics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Proteins
MH  - Swine
MH  - Thrombin
MH  - Thrombosis/drug therapy
MH  - Ticks/*genetics/*metabolism
MH  - *Transcriptome
PMC - PMC8617063
COIS- Part of the work related to the peptides as thrombin inhibitors was included in 
      the patent application with C.Y.K., J.K.I. and R.M.K. among the inventors 
      (WO2016204696A1 Novel thrombin inhibitors). Antibodies tested as reversal agents 
      for ultravariegin were included in another patent application with C.Y.K., V.V., 
      A.G., V.K.C., R.M.K. and M.Y.C. among the inventors (application in progress). 
      The remaining authors declare no competing interests.
EDAT- 2021/11/27 06:00
MHDA- 2022/01/04 06:00
PMCR- 2021/11/25
CRDT- 2021/11/26 06:19
PHST- 2021/01/25 00:00 [received]
PHST- 2021/10/28 00:00 [accepted]
PHST- 2021/11/26 06:19 [entrez]
PHST- 2021/11/27 06:00 [pubmed]
PHST- 2022/01/04 06:00 [medline]
PHST- 2021/11/25 00:00 [pmc-release]
AID - 10.1038/s41467-021-27275-8 [pii]
AID - 27275 [pii]
AID - 10.1038/s41467-021-27275-8 [doi]
PST - epublish
SO  - Nat Commun. 2021 Nov 25;12(1):6912. doi: 10.1038/s41467-021-27275-8.