Abstract
The integrin αIIbβ3 is the most abundant integrin on platelets. Upon platelet activation, the integrin changes its conformation (inside-out signalling) and outside-in signalling takes place leading to platelet spreading, platelet aggregation and thrombus formation. Bloodsucking parasites such as mosquitoes, leeches and ticks express anticoagulant and antiplatelet proteins, which represent major sources of lead compounds for the development of useful therapeutic agents for the treatment of haemostatic disorders or cardiovascular diseases. In addition to hematophagous parasites, snakes also possess anticoagulant and antiplatelet proteins in their salivary glands. Two snake venom proteins have been developed into two antiplatelet drugs that are currently used in the clinic. The group of proteins discussed in this review are disintegrins, low molecular weight integrin-binding cysteine-rich proteins, found in snakes, ticks, leeches, worms and horseflies. Finally, we highlight various oral antagonists, which have been tested in clinical trials but were discontinued due to an increase in mortality. No new αIIbβ3 inhibitors are developed since the approval of current platelet antagonists, and structure-function analysis of exogenous disintegrins could help find platelet antagonists with fewer adverse side effects.
Highlights
Integrins are an important class of transmembrane glycoprotein (GP) receptors consisting of an alpha- and a beta subunit, both of which have an extracellular domain, a transmembrane domain and a cytoplasmic domain
For the prevention of thrombotic complications in patients suffering from acute coronary syndrome or unstable angina pectoris, the integrin αIIbβ3 antagonists abciximab, eptifibatide and tirofiban are occasionally used in the clinical setting
Eptifibatide and tirofiban, based on the ligand (RGD)-mimetics, bind to the integrin with low affinity and induce a conformational change, which results in outside-in signalling and paradoxical platelet activation [135]
Summary
Integrins are an important class of transmembrane glycoprotein (GP) receptors consisting of an alpha- and a beta subunit, both of which have an extracellular domain, a transmembrane domain and a cytoplasmic domain. The α-subunits can be divided into two groups: subunits with an inserted domain (αI) and subunits without an inserted domain This domain has a metal ion-dependent adhesion site (MIDAS), which allows ligands to bind the receptor [3]. The αvβ and αIIbβ are β3 integrins, where αIIbβ (GPIIb/IIIa, CD41/CD61) is the most abundant integrin on platelets [1,8,9]. The α-subunit of αIIbβ consists of 1008 amino acids and contains a cytoplasmic tail, a transmembrane domain, two calf domains, a thigh domain and a head (a β-propeller domain), which is the main ligand-binding domain (Figure 1) [2,15]. Integrin αIIbβ plays a crucial role in platelet adhesion and platelet aggregation. Sci. 2021, 22, 3366 take place, exposing the ligand-binding site of the fibrinogen receptor, which is unavailable in resting platelets, and as a consequence, fibrinogen crosslinks multiple platelets into aggregates, forming a platelet plug [23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
