Delcasertib

A disulfide-bridged peptide drug development candidate contained two oligopeptide chains with 11 and 12 natural amino acids joined by a disulfide bond at the N-terminal end. An efficient biotechnology based process for the production of the disulfide-bridged peptide was developed. Initially, the two individual oligopeptide chains were prepared separately by designing different fusion proteins and expressing them in recombinant E. coli. Enzymatic or chemical cleavage of the two fusion proteins provided the two individual oligopeptide chains which could be conjugated via disulfide bond by conventional chemical reaction to the disulfide-bridged peptide. A novel heterodimeric system to bring the two oligopeptide chains closer and induce disulfide bond formation was designed by taking advantage of the self-assembly of a leucine zipper system. The heterodimeric approach involved designing fusion proteins with the acidic and basic components of the leucine zipper, additional amino acids to optimize interaction between the individual chains, specific cleavage sites, specific tag to ensure separation, and two individual oligopeptide chains. Computer modeling was used to identify the nature and number of amino acid residue to be inserted between the leucine zipper and oligopeptides for optimum interaction. Cloning and expression in rec E. coli, fermentation, followed by cell disruption resulted in the formation of heterodimeric protein with the interchain disulfide bond. Separation of the desired heterodimeric protein, followed by specific cleavage at methionine by cyanogen bromide provided the disulfide-bridged peptide.

This editorial refers to ‘Inhibition of delta-protein kinase C by delcasertib as an adjunct to primary percutaneous coronary intervention for acute anterior ST-segment elevation myocardial infarction: results of the PROTECTION AMI Randomized Controlled Trial’[†][1], by A.M. Lincoff et al. , on page 2516 Reperfusion therapy reduces infarct size and improves left ventricular function in ST-segement elevation myocardial infarction (STEMI). Despite restoration of epicardial perfusion and commensurate reductions in morbidity and mortality, residual hazard persists. Restoration of coronary blood flow after prolonged ischaemia may exhibit a ‘double edge’ characterized as reperfusion injury with resulting cell death that can account for up to half of the final infarct size.1 The pathophysiology of reperfusion injury is probably multifactorial and includes distal embolization/platelet plugging of the microvasculature, release of toxic inflammatory mediators, production of oxygen free radicals, and accumulation of intracellular calcium. Whereas various cytoprotective agents have shown promise in animal models, to date translation of this benefit has been disappointing at best.2 Hence, combating reperfusion injury remains one of the final therapeutic frontiers in STEMI management. Because protein kinase C (PKC) isoenzymes modulate myocardial protection, their potential for therapeutic intervention has been of interest.3,4 However, counter-regulatory cardioprotective activity has been reported with specific PKC isoenzymes. This ‘ying–yang’ counterpoint is represented by activation of ePKC which provides cardioprotection whereas activation of δPKC induces myocardial cell damage following ischaemia.5 Application of this pathway to myocardial protection led to the development of the selective δPKC antagonist, delcasertib, which reduced infarct size and improved microvascular function following reperfusion in animal models.6,7 Given the experimental promise of delcasertib, a phase II dose-escalation study of 154 patients … [1]: #fn-2