New synthetic peptide with efficacy for heparin reversal and low toxicity and immunogenicity in comparison to protamine sulfate

Li, Tong; Zhang, Meng; Zhu, Xue-Ming; Gan, Hui; Gu, Ruixia; Wu, Zhiyong; Li, Jian; Zheng, Ying; Liu, Taoyun; Han, Peng; Han, Shuang; Dou, Guifang

doi:10.1016/j.bbrc.2015.10.020

Cited by 10 publications

(10 citation statements)

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“…R15 can be degraded by carboxypeptidase that cleaves off the C‐terminal arginine residue [46]. The main metabolites of R15 were R12, R13, and R14, which also possess the binding ability of UFH [21]. Further studies are needed to monitor heparin rebound in large animals (dogs or monkeys) with extended observation times.…”

Section: Discussionmentioning

confidence: 99%

“…A modified procedure that was described elsewhere was followed [21]. In brief, 24 Wistar rats were randomized into 4 groups (six rats per group).…”

Section: Potency Verification In Rats In Vivomentioning

confidence: 99%

“…Other candidates, including recombinant inactive antithrombin, poly‐l‐lysine, and low‐molecular‐weight protamine, exhibit the ability to reverse UFH in animals [18–20]. Previously, we reported the potential UFH antagonist R15 (a linear peptide composed of 15 arginine) that has similar efficacy and avoids immunogenicity in comparison with PS [21]. In this article, the factors mentioned above, as well as the efficacy–toxicity relationship, were considered to design the experiments.…”

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confidence: 99%

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In vitro and in vivo safety studies indicate that R15, a synthetic polyarginine peptide, could safely reverse the effects of unfractionated heparin

Zhang

Zhu

et al. 2021

FEBS Open Bio

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Unfractionated heparin (UFH) is an anionic glycosaminoglycan that is widely used to prevent blood clotting. However, in certain cases, unwanted side effects can require it to be neutralized. Protamine sulfate (PS), a basic peptide rich in arginine, is the only approved antagonist for UFH neutralization.Many adverse reactions occur with the clinical application of PS, including systemic hypotension, pulmonary hypertension and anaphylaxis. We previously described R15, a linear peptide composed of 15 arginine molecules, as a potential UFH antagonist. In this study, the in-depth safety of R15 was explored to reveal its merits and associated risks in comparison with PS. In vitro safety studies investigated the interactions of R15 with erythrocytes, fibrin, complement and rat plasma. In vivo safety studies explored potential toxicity and immunogenicity of R15 and the UFH-R15 complex.Results showed that both PS and R15 can induce erythrocyte aggregation, thicken fibrin fibers, activate complement and cause anti-coagulation in a concentration-dependent manner. However, those influences weakened in whole blood or in live animals, and were avoided when R15 was in a complex with UFH. We found dramatically enhanced complement activation when there was excess UFH in analyses involving UFH-PS complexes, and a slight increase in those involving UFH-R15 complexes. Within 2 hours, R15 was degraded in rat plasma in vitro, whereas PS was not. Enhanced creatinine was found after a single intravenous injection of PS or R15 (900 U•kg -1 , body weight), suggesting possible abnormal renal function. The UFH-PS complex, but not the UFH-R15 complex, exhibited obvious immunogenicity. In conclusion, R15 is non-immunogenic and potentially safe at a therapeutic dose to reverse the effects of UFH.

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Section: Discussionmentioning

confidence: 99%

“…A modified procedure that was described elsewhere was followed [21]. In brief, 24 Wistar rats were randomized into 4 groups (six rats per group).…”

Section: Potency Verification In Rats In Vivomentioning

confidence: 99%

mentioning

confidence: 99%

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In vitro and in vivo safety studies indicate that R15, a synthetic polyarginine peptide, could safely reverse the effects of unfractionated heparin

Zhang

Zhu

et al. 2021

FEBS Open Bio

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“…28 Short peptides can be directly derived or inspired by protamine, whose arginine content is 67%. Protamine mimics consisting of 3 to 20 arginine residues were prepared by Dou et al, 29 who found that a minimum of eight arginine residues was required to observe anti-UFH activities. The (Arg) 15 -based peptide was then compared to protamine in vivo on rats.…”

Section: ■ Context and Challengesmentioning

confidence: 99%

Lost in (Clinical) Translation: Recent Advances in Heparin Neutralization and Monitoring

Ourri

Vial

2019

ACS Chem. Biol.

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The heparin family, which includes unfractionated heparin, low-molecular heparin and fondaparinux, is a class of drugs clinically used as intravenous blood thinner. To date, issues related to both to the reversal of anticoagulation and the blood level determination of the anticoagulant at the point-of-care remain: while the only U.S. Food and Drug Administration (FDA) approved antidote for heparin displays serious efficacy and safety drawbacks, the current assays for heparin monitoring are indirect measurements subject to their own limitations and variations. Herein, we provide an update on the numerous recent chemical approaches to tackle these issues, from which it is clear that some new antidotes and sensors for heparin certainly have the potential to exceed current clinical standards. This review aims to review a field that requires close collaborations between physicians, biologists and chemists in order to foster advances toward clinical translation. Context and challengesHeparin, which belongs to the family of glycosaminoglycans (GAGs), is a linear sulfated polysaccharide and consists of repeating disaccharide subunits of α-1,4 linked uronic acid and D-glucosamine (Figure 1). As a consequence, heparin displays the highest density of negative charges among biomacromolecules. This polyanion is widely used as an intravenous anticoagulant due to its ability to accelerate the rate at which antithrombin (AT) inhibits serine proteases within the blood coagulation cascade, most notably factor Xa and thrombin. [1][2][3][4] Polymers of various lengths such as unfractionated heparin (UFH, Mw ~ 15 kDa), low-molecular-weight heparins (LMWHs, Mw = 3.6-6.5 kDa), and the synthetic pentasaccharide fondaparinux (Mw = 1.7 kDa) are routinely delivered to patients. While UFH is used during acute thrombotic events or to maintain blood fluidity during procedures requiring extracorporeal circulation (i.e., cardio-pulmonary bypass or hemodialysis), 5,6 LMWHs and fondaparinux are prescribed to treat and/or prevent deep vein thrombosis and pulmonary embolism. 7,8 With an estimated one billion doses of heparin produced every year, heparin's market is rapidly growing, driven by the ageing of populations and the increasing incidence of cardiovascular diseases. 9 KeywordsAnticoagulants: commonly known as blood thinners, they are chemical substances that retard or inhibit the coagulation of the blood.

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“… 8 − 10 However, the number of antidotes for heparin-type drugs is quite limited: the one mostly used is protamine, 11 a small arginine-rich nuclear protein. Recent reports on alternative macromolecules to reverse heparin drugs include a polymeric polycationic dendrimer (UHRA), 12 a monoclonal antibody (idarucizumab), 13 a modified version of the recombinant human coagulation factor Xa (andexanet alpha), 14 as well as peptides 15 and peptidomimetics 16 mimicking protamine. Other representative Hep-binding molecular scaffolds are self-assembled cationic amphiphiles 17 or peptide dendrimers.…”

Section: Introductionmentioning

confidence: 99%

Dynamic Combinatorial Optimization of In Vitro and In Vivo Heparin Antidotes

Carbajo¹,

Pérez²,

Guerra-Rebollo

et al. 2022

J. Med. Chem.

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Heparin-like macromolecules are widely used in clinics as anticoagulant, antiviral, and anticancer drugs. However, the search of heparin antidotes based on small synthetic molecules to control blood coagulation still remains a challenging task due to the physicochemical properties of this anionic polysaccharide. Here, we use a dynamic combinatorial chemistry approach to optimize heparin binders with submicromolar affinity. The recognition of heparin by the most amplified members of the dynamic library has been studied with different experimental (SPR, fluorescence, NMR) and theoretical approaches, rendering a detailed interaction model. The enzymatic assays with selected library members confirm the correlation between the dynamic covalent screening and the in vitro heparin inhibition. Moreover, both ex vivo and in vivo blood coagulation assays with mice show that the optimized molecules are potent antidotes with potential use as heparin reversal drugs. Overall, these results underscore the power of dynamic combinatorial chemistry targeting complex and elusive biopolymers.

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New synthetic peptide with efficacy for heparin reversal and low toxicity and immunogenicity in comparison to protamine sulfate

Cited by 10 publications

References 20 publications

In vitro and in vivo safety studies indicate that R15, a synthetic polyarginine peptide, could safely reverse the effects of unfractionated heparin

In vitro and in vivo safety studies indicate that R15, a synthetic polyarginine peptide, could safely reverse the effects of unfractionated heparin

Lost in (Clinical) Translation: Recent Advances in Heparin Neutralization and Monitoring

Dynamic Combinatorial Optimization of In Vitro and In Vivo Heparin Antidotes

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