000131680 001__ 131680
000131680 005__ 20241125101140.0
000131680 0247_ $$2doi$$a10.1016/j.ejmech.2023.115837
000131680 0248_ $$2sideral$$a137044
000131680 037__ $$aART-2023-137044
000131680 041__ $$aeng
000131680 100__ $$aPinheiro, Francisca
000131680 245__ $$aPITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties
000131680 260__ $$c2023
000131680 5060_ $$aAccess copy available to the general public$$fUnrestricted
000131680 5203_ $$aThe aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities. In an effort to endorse the previously developed molecules with optimal pharmacokinetic properties, we conducted structural design optimization, leading to the development of PITB. PITB binds with high affinity to TTR, effectively inhibiting tetramer dissociation and aggregation of both the wild-type protein and the two most prevalent disease-associated TTR variants. Importantly, PITB selectively binds and stabilizes TTR in plasma, outperforming tolcapone, a drug currently undergoing clinical trials for ATTR. Pharmacokinetic studies conducted on mice confirmed that PITB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PITB demonstrates excellent oral bioavailability and lack of toxicity. These combined attributes position PITB as a lead compound for future clinical trials as a disease-modifying therapy for ATTR.
000131680 536__ $$9info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PDC2021-120914-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PID2021-124602OB-I00$$9info:eu-repo/grantAgreement/ES/MINECO/PID2019-106403RB-I00
000131680 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000131680 590__ $$a6.0$$b2023
000131680 592__ $$a1.151$$b2023
000131680 591__ $$aCHEMISTRY, MEDICINAL$$b8 / 72 = 0.111$$c2023$$dQ1$$eT1
000131680 593__ $$aDrug Discovery$$c2023$$dQ1
000131680 593__ $$aPharmacology$$c2023$$dQ1
000131680 593__ $$aOrganic Chemistry$$c2023$$dQ1
000131680 593__ $$aMedicine (miscellaneous)$$c2023$$dQ1
000131680 594__ $$a11.7$$b2023
000131680 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000131680 700__ $$aVarejão, Nathalia
000131680 700__ $$aSánchez-Morales, Adrià
000131680 700__ $$aBezerra, Filipa
000131680 700__ $$aNavarro, Susanna
000131680 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez-Campoy, Adrián$$uUniversidad de Zaragoza
000131680 700__ $$aBusqué, Félix
000131680 700__ $$aAlmeida, Maria Rosário
000131680 700__ $$aAlibés, Ramon
000131680 700__ $$aReverter, David
000131680 700__ $$aPallarès, Irantzu
000131680 700__ $$aVentura, Salvador
000131680 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000131680 773__ $$g261 (2023), 115837 [10 pp.]$$pEur. j. med. chem.$$tEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY$$x0223-5234
000131680 8564_ $$s5913299$$uhttps://zaguan.unizar.es/record/131680/files/texto_completo.pdf$$yVersión publicada
000131680 8564_ $$s2535080$$uhttps://zaguan.unizar.es/record/131680/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000131680 909CO $$ooai:zaguan.unizar.es:131680$$particulos$$pdriver
000131680 951__ $$a2024-11-22-12:02:29
000131680 980__ $$aARTICLE