title: Rational design of the first difluorostatone-based PfSUB1 inhibitors.
abstract: The etiological agent of the most dangerous form of malaria, Plasmodium falciparum, has developed resistance or reduced sensitivity to the majority of the drugs available to treat this deadly disease. Innovative antimalarial therapies are therefore urgently required. P. falciparum serine protease subtilisin-like protease 1 (PfSUB1) has been identified as a key enzyme for merozoite egress from red blood cells and invasion. We present herein the rational design, synthesis, and biological evaluation of novel and potent difluorostatone-based inhibitors. Our bioinformatic-driven studies resulted in the identification of compounds 1a, b as potent and selective PfSUB1 inhibitors. The enzyme/inhibitor interaction pattern herein proposed will pave the way to the future optimization of this class of promising enzyme inhibitors.
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Giovani
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Penzo
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy. Electronic address: gemma@unisi.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dip. di Farmacia, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Savini
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy. Electronic address: campiani@unisi.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013381:Subtilisins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D013381:Subtilisins; C403176:subtilisin-like protease 1, Plasmodium falciparum
keywords: Difluorostatone; Egress; Malaria; PfSUB1; Serine protease