Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming

Ford, Daniel; Duggan, Nisharnthi M; Fry, Sarah E.; Ripoll‐Rozada, Jorge; Agten, Stijn M.; Liu, Wenyu; Corcilius, Leo; Hackeng, Tilman M.; Oerle, René van; Spronk, Henri M. H.; Ashhurst, Anneliese S.; Sasi, Vishnu Mini; Kaczmarski, Joe A.; Jackson, C.J.; Pereira, Pedro José Barbosa; Passioura, Toby; Suga, Hiroaki; Payne, Richard J.

doi:10.1021/acs.jmedchem.1c00651

Cited by 16 publications

(12 citation statements)

References 47 publications

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“…CAS (Seo et al, 2019) is generally considered to be a passive defense system of the body against foreign substances, and its performance in the coagulation process is as follows: Conduction occurs when blood comes into contact with a negatively charged surface (Grover and Mackman, 2019) (such as some foreign proteins or materials, etc. ), which activates the surface factor (FXII) to FXIIa (Ford et al, 2021). Subsequently, with the help of high molecular weight kininogen (HK) (Ponczek, 2021), FXIIa activates prekallikrein (PK) (Wang et al, 2022) to form plasma-type kallikrein (KAL) (Griesbacher et al, 2008).…”

Section: Coagulation Processmentioning

confidence: 99%

Discovery and development of Factor Xa inhibitors (2015–2022)

Zheng

Dai

et al. 2023

Front. Pharmacol.

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As a pathological coagulation process, thrombus can lead to many serious diseases, including ischemic stroke, acute myocardial infarction (AMI), acute coronary syndrome (ACS), and deep venous thrombosis (DVT). And anticoagulant drugs are one of the most effective ways to prevent and treat these diseases. Although macromolecular anticoagulant drugs such as low molecular weight heparins (LMWHs) are widely used in the clinic, their characteristics of requiring injectable use hinder their further promotion in the clinic, and the disadvantages of oral anticoagulant drugs, such as warfarin and dabigatran etexilate, which can easily cause bleeding adverse effects, are also not addressed. Factor Xa (FXa) has gained attention because it lies at the intersection of the coagulation cascade pathways, whereas subsequently introduced Factor Xa inhibitors such as rivaroxaban and apixaban, among others, have gained market popularity because of their high potency for anticoagulation and high specificity for Factor Xa when administered orally. But some of the drawbacks that these Factor Xa inhibitors have simultaneously such as fewer indications and the lack of an effective reversal drug when bleeding occurs are urgently addressed. The development of new Factor Xa inhibitors therefore becomes one means of addressing these questions. This article summarizes the small molecule Factor Xainhibitors developed from 2015 to 2022, classifies them according to their scaffolds, focuses on the analysis of their structure-activity relationships, and provides a brief assessment of them.

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Section: Coagulation Processmentioning

confidence: 99%

Discovery and development of Factor Xa inhibitors (2015–2022)

Zheng

Dai

et al. 2023

Front. Pharmacol.

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“…As the air temperature being sensed by the probe does not increase, the reactor will continue to irradiate at full power throughout the experiment, overheating the samples. The sample was irradiated.The plate was removed from the microwave reactor, and the resin was washed as in steps [6][7][8][9][10][11].…”

Section: Crictical Stepmentioning

confidence: 99%

A Review on Peptide Synthesis: Therapeutic agents, stabilizing agents and its applications

T¹,

Khaleel²,

Ramesh³

et al. 2023

J Integral Sci

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Peptides are required as a part of health through their extended activity. Peptides are also purified because of their high target affinity. The synthesis includes both the conventional method and the microwave method among which microwave procedure is considered superior due to less reaction time and higher yeilds. The peptides were assessed for the inhibition activity of Urokinase plasminogen (UpA), coagulation factor XII, and also for the cytotoxicity and anti-microbial activity.

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“…Recently, the Suga lab harnessed the RaPID system to potent and selective inhibitors of the catalytic domain of factor XIIa (FXIIa), an important target for the development of antithrombotics (Figure ). − Following iterative rounds of screening, six peptides were identified and synthesized on resin for assessing their inhibitory activity against human αFXIIa using a continuous colorimetric assay. In this assay, a caged chromogenic substrate is used, which, upon hydrolysis by FXIIa, liberates p -nitroaniline that can be quantified by UV absorbance.…”

Section: The Rise Of Bioactive Cyclic Peptidesmentioning

confidence: 99%

Cyclic Peptide Screening Methods for Preclinical Drug Discovery

Craven

Levine

2022

J. Med. Chem.

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Cyclic peptides are among the most diverse architectures for current drug discovery efforts. Their size, stability, and ease of synthesis provide attractive scaffolds to engage and modulate some of the most challenging targets, including protein–protein interactions and those considered to be “undruggable”. With a variety of sophisticated screening technologies to produce libraries of cyclic peptides, including phage display, mRNA display, split intein circular ligation of peptides, and in silico screening, a new era of cyclic peptide drug discovery is at the forefront of modern medicine. In this perspective, we begin by discussing cyclic peptides approved for clinical use in the past two decades. Particular focus is placed around synthetic chemistries to generate de novo libraries of cyclic peptides and novel methods to screen them. The perspective culminates with future prospects for generating cyclic peptides as viable therapeutic options and discusses the advantages and disadvantages currently being faced with bringing them to market.

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Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming

Cited by 16 publications

References 47 publications

Discovery and development of Factor Xa inhibitors (2015–2022)

Discovery and development of Factor Xa inhibitors (2015–2022)

A Review on Peptide Synthesis: Therapeutic agents, stabilizing agents and its applications

Cyclic Peptide Screening Methods for Preclinical Drug Discovery

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