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Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
Gunatilleke et al. (2012) combined target-based high-throughput screening (HTS) with a screen against T. cruzi-infected skeletal myoblast cells to yield compounds with a known molecular target and activity against the parasite. Further, they used bioinformatics approaches to demonstrate similarities between compounds preferentially bound by CYP51 and compounds bound by several other cytochrome P450 enzymes and an unrelated glutaminyl-peptide cyclotransferase. Inhibitors of these enzymes can hence serve as a potential pool of lead compounds.
The overall potential of CD47 in cancer immunotherapy: with a focus on gastrointestinal tumors
Published in Expert Review of Anticancer Therapy, 2019
Emmanouil Tzatzarakis, Barbara Hissa, Christoph Reissfelder, Sebastian Schölch
Anti-CD47 antibody therapy, however, faces a major obstacle: due to the abundance of CD47 protein on virtually all cells of the body including red blood cells, there is a tremendous antigen sink reducing the activity of CD47 antibodies. Vast amounts of antibodies are required in order to achieve therapeutic concentrations, which may ultimately become an economical challenge to healthcare systems, should the indications of CD47 mAbs be as frequent as those of other checkpoint inhibitors. An alternative may be SIRPα-blocking antibodies, as SIRPα is present only in myeloid cells. Another promising strategy is the inhibition of the post-translational modification of CD47 by glutaminyl-peptide cyclotransferase-like protein (QPCTL), a protein responsible for post-translational pyroglutamate formation at the SIRPα binding site of CD47 [55]. QCPTL inhibitors are currently in clinical trials for neurodegenerative diseases and are generally well tolerated [56]. Inhibition of QPCTL abolishes CD47 signaling, leads to increased neutrophil-mediated killing of cancer cells in vivo and is, therefore, a promising alternative to CD47 antibodies [55].