Applications of new desferrioxamine derivatives with high cell permeability

• Grant number: 18/19684-0
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2019
• End date: December 31, 2021
• Field of knowledge: Health Sciences - Pharmacy - Pharmacognosy
• Principal Investigator: Breno Pannia Esposito
• Grantee: Breno Pannia Esposito
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Iron overload is a debilitating condition for patients, leading to decreased quality of life. At the same time, iron is a crucial nutrient also for parasites and tumor cells. Iron chelators are high affinity molecules that display several possibilities of clinical use: (i) reducing metal overload; (ii) delivering toxic metals to selected targets; (iii) scavenging essential metals from said targets. Desferrioxamine (DFO), a bacterial siderophore, was the first clinically approved iron chelator, displaying high affinity for Fe(III). However, its use is hampered since it has low cell permeability and low gastrointestinal absorption. Our laboratory developed two DFO derivatives with high cell permeability, DFO-caffeine (DFCAF) and DFO-triphenylphosphonium (TPP-DFO), aimed at the blood-brain barrier and mitochondria, respectively. In this project, we propose to follow up with the studies for both conjugates, by studying their permeability profiles in artificial membranes (PAMPA systems), seeking new pharmacological applications against neglected diseases (anti-leishmanial, anti-chagasic, anti-malarial, anti-tuberculosis and anti-leprosy) based on their ability to disturb iron metabolism, and conducting in vivo experiments in models of iron overload. To that end, national and international collaborations with experts in each area have been established. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

JOSE MIGUEL DIAZ ROMERO; MARINA TONETTI BOTANA; ALINE DE CARVALHO ELIAS; CASSIANA SEIMI NOMURA; FLÁVIA SALDANHA-CORRÊA; BRENO PANNIA ESPÓSITO. Effect of iron speciation on growth and heat resistance of Symbiodiniaceae. Ocean and Coastal Research, v. 70, 2022-05-06. (21/10894-5, 18/19684-0)

CARVALHO, RODRIGO R. V.; PERES, TANARA V.; LIRIA, CLEBER W.; MACHINI, M. TERESA; ASCHNER, MICHAEL; ESPOSITO, BRENO P.. Conjugates of desferrioxamine and aromatic amines improve markers of iron-dependent neurotoxicity. BIOMETALS, v. 34, n. 2, JAN 2021. (15/14360-4, 18/19684-0, 16/03709-9)

ESPOSITO, BRENO PANNIA; MARTINS, AIRTON CUNHA; DE CARVALHO, RODRIGO RODRIGUES VICTOR; ASCHNER, MICHAEL. High throughput fluorimetric assessment of iron traffic and chelation in iron-overloadedCaenorhabditis elegans. BIOMETALS, v. 33, n. 4-5, p. 255-267, OCT 2020. (18/19684-0)

SILVA, FREDSON TORRES; ESPOSITO, BRENO PANNIA. Intracellular Iron Binding and Antioxidant Activity of Phytochelators. BIOLOGICAL TRACE ELEMENT RESEARCH, OCT 2021. (18/19684-0)