Abstract
Scaffold-based peptides (SBPs) are fragments of large proteins that are characterized by potent bioactivity, high thermostability, and low immunogenicity. Some SBPs have been approved by the FDA for human use. In the present study, we developed SBPs from the venom gland of Deinagkistrodon acutus (D. acutus) by combining transcriptome sequencing and Pfam annotation. To that end, 10 Kunitz peptides were discovered from the venom gland of D. acutus, and most of which peptides exhibited Factor XIa (FXIa) inhibitory activity. One of those, DAKS1, exhibiting strongest inhibitory activity against FXIa, was further evaluated for its anticoagulant and antithrombotic activity. DAKS1 prolonged twofold APTT at a concentration of 15 μM in vitro. DAKS1 potently inhibited thrombosis in a ferric chloride-induced carotid-artery injury model in mice at a dose of 1.3 mg/kg. Furthermore, DAKS1 prevented stroke in a transient middle cerebral-artery occlusion (tMCAO) model in mice at a dose of 2.6 mg/kg. Additionally, DAKS1 did not show significant bleeding risk at a dose of 6.5 mg/kg. Together, our results indicated that DAKS1 is a promising candidate for drug development for the treatment of thrombosis and stroke disorders.
Highlights
Scaffold-based peptides are fragments of large proteins that play an important role in biological processes, and are characterized by high thermostability and low immunogenicity [1,2,3]
Kunitz domains are derived from the active motif of Kunitz-type protease inhibitors, and they mainly inhibit the function of protein-degrading enzymes or, they are serine protease inhibitors [7,8,9]
Ten Kunitz SBPs Discovered from Venom Gland of D. acutus
Summary
Scaffold-based peptides are fragments of large proteins that play an important role in biological processes, and are characterized by high thermostability and low immunogenicity [1,2,3] Their structures are similar to those of antibodies; each scaffold includes a constant region, which provides a stable secondary structure, and one or more variable loops, which are a response for binding to given targets. Some of these SBPs were approved by the FDA for human use [4,5], and many are currently being evaluated preclinically or in clinical trials, such as Kunitz domains, adnectins, anticalins, avimers, Fynomers, knottins, affibodies, β-hairpin mimetics, and DARPins [2,6]. Kunitz SBPs are promising compounds for the treatment of serine protease-related diseases
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
