https://hdl.handle.net/10481/31132 Fri, 17 Apr 2026 05:57:22 GMT 2026-04-17T05:57:22Z https://hdl.handle.net/10481/111200 Targeting Oxalate Production by Combining Enzyme Inhibition and Proteolysis Activation: A Novel Therapeutic Approach for Primary Hyperoxaluria Type 1 Arias Bordajandi, Fabio; Sixto-López, Yudibeth; Richard, Koral S. E.; Das, Sandeep; Anand, Sumit K.; Luque Navarro, Pilar María; Bañuelos Sánchez, Guillermo; Pacheco García, Juan Luis; Gade, Reethika; McKinney, M. Peyton; Kumar, Dhananjay; Maxie, Jemiah; Corr, W. Rylan; Pandey, Nilesh; Kaur, Harpreet; Ding, Jibin; Tan, Lin; Scott, Elisha; Nam, Hyung; Gottlieb, Eyal; Orr, A. Wayne; Dhanesha, Nirav; Yurdagul, Arif; Pey Rodríguez, Ángel Luis; Franco Montalbán, Francisco; Gómez Vidal, José Antonio; Rom, Oren; Díaz Gavilán, Mónica Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by hepatic oxalate overproduction due to alanine-glyoxylate aminotransferase (AGXT) deficiency. Therapeutic strategies targeting glycolate oxidase (GO) and lactate dehydrogenase A (LDHA), key enzymes in glyoxylate metabolism, have shown promise in reducing oxalate burden. However, recently approved siRNA therapies remain limited by high cost, unfavorable pharmacokinetics, and limited global accessibility. We report the development of compound 2, a dual GO/LDHA inhibitor (Ki = 390 and 40 nM, respectively) that also promotes hydrophobic tag-mediated autophagic degradation of LDHA. Its efficacy was evaluated in Agxt–/– mice, both in primary hepatocytes and through oral administration. Treatment significantly reduced hepatic LDHA levels, urinary oxalate excretion, and renal calcium-oxalate crystal deposition. These findings support compound 2 as a first-in-class, orally bioavailable small molecule with dual inhibitory and proteolytic activity, offering a novel therapeutic candidate for PH1 and other oxalate-related pathologies. This study was partially supported by grant PID2022–141783OB-C21 funded by MICIU/AEI/10.13039/501100011033 and by “ERDF/EU” (M.D.G; with salary/contract support for Y.S.L. and P.L.N.); National Institutes of Health (NIH) grants DK136685 (O.R.), DK134011 (O.R.) HL150233 (O.R.), HL180481 (A.Y.J.), HL167758 (A.Y.J.), HL145131 (A.Y.J.); National Science Foundation grant 2537597 (A.Y.J., N.D., A.W.O., and O.R.); the LSUHS Center for Cardiovascular Diseases and Sciences Malcolm Feist Postdoctoral Fellowship (S.R.); NIH Predoctoral T32 Fellowship HL155022 (K.S.E.R.); and the American Heart Association Postdoctoral Fellowships 24POST1196650 (S.D.), 24POST1199805 (S.K.A.) and 25POST1352845 (D.K.). Universidad de Granada / CBUA. https://hdl.handle.net/10481/111200 https://hdl.handle.net/10481/109425 New N-Alkylketonetetrahydroisoquinoline derivatives exhibits antitumor effect by HA-CD44 interaction inhibition in MDA-MB-231 breast cancer Chayah Ghaddab, Meriem; Espejo Román, José Manuel; Erviti Marticorena, Laura; Huertas Camarasa, Felipe José; Domene, Carmen; Sánchez Martín, Rosario María; Conejo García, Ana; Cruz López, Olga María Molecular interactions at the cell surface, in particular between hyaluronic acid (HA) and the cluster of differentiation 44 (CD44) receptor, are crucial in several biological processes and diseases such as cancer. Thus, inhibition of the HA-CD44 interaction has become a promising therapeutic strategy. Etoposide was the only antitumor compound known to inhibit the binding of CD44 to HA, thereby disrupting key functions that drive malignancy. However, our recent research led to the development of N-alkyl and N-aryl THIQ derivatives, which represented a significant advancement in this field. Here, we further explore the structure–activity relationships of a series of newly designed N-alkylcarbonyl THIQ and study the structural parameters that define both the CD44 inhibitory and antiproliferative activities. Compounds 5d and 7d showed the most improvement of the antiproliferative activity compared to the N-alkylketone 1. Cell viability, competitive binding assays and molecular dynamics studies demonstrated effective inhibition of HA-CD44 binding by compounds 5d and 7d. This work not only expands the arsenal of potential therapeutic agents targeting HA-CD44 interactions but also highlights the potential for new treatments that could more effectively disrupt cancer progression. This work was funded by the project PID2021.128109OB.I00 financed by MICIU/AEI/10.13039/501100011033, and the project P18-RT-1679 financed by the Consejería de Universidad, Investigación e Innovación of the Junta de Andalucía and by ERDF A way of making Europe. C.D. thanks HECBioSim, the UK High End Computing Consortium for Biomolecular Simulation (hecbiosim.ac.uk), which is supported by the EPSRC EP/L000253/1 for awarding computing time in Jade, the Joint Academic Data science Endeavour (JADE) service and Bede, two of the UK’s regional Tier 2 high-performance computing facilities. The support of the N8 Centre of Excellence for Computationally Intensive Research (N8 CIR) funded by the N8 research partnership is gratefully acknowledged. https://hdl.handle.net/10481/109425 https://hdl.handle.net/10481/107604 O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity Corpas-López, Victoriano; Tabraue-Chavez, Mavys; Sixto-López, Yudibeth; Panadero-Fajardo, Sonia; Alves de Lima Franco, Fernando; Domínguez Seglar, José Francisco; Morillas Márquez, Francisco; Franco Montalbán, Francisco; Díaz Gavilán, Mónica; Correa-Basurto, José; López-Viota, Julián; López-Viota Gallardo, Margarita; Pérez del Palacio, José; de la Cruz, Mercedes; de Pedro, Nuria; Martín Sánchez, Joaquina; Gómez Vidal, José Antonio Leishmania (L.) infantum causes visceral, cutaneous, and mucosal leishmaniasis in humans and canine leishmaniasis in dogs. Herein, we describe that O-alkyl hydroxamate derivatives displayed potent and selective in vitro activity against the amastigote stage of L. infantum while no activity was observed against promastigotes. Compound 5 showed potent in vivo activity against L. infantum. Moreover, the combination of compound 5 supported on gold nanoparticles and meglumine antimoniate was also effective in vivo and improved the activity of these compounds compared to that of the individual treatment. Docking studies showed that compound 5 did not reach highly conserved pocket C and established interactions with the semiconserved residues V44, A45, R242, and E243 in pocket A of LiSIR2rp1. The surface space determined by these four amino acids is not conserved in human sirtuins. Compound 5 represents a new class of selective ligands with antileishmanial activity. Versión del autor (manuscrito aceptado) depositada conforme a la política de autoarchivo de la editorial American Chemical Society (ACS Publications) para el Journal of Medicinal Chemistry (ver: https://openpolicyfinder.jisc.ac.uk/id/publication/7786 ). De acuerdo con dicha política, el autor puede depositar en repositorios institucionales la versión aceptada del manuscrito tras un embargo de 12 meses desde la publicación. Dado que el artículo fue publicado en 2020, el periodo de embargo ha finalizado y esta versión puede difundirse en acceso abierto. https://hdl.handle.net/10481/107604 https://hdl.handle.net/10481/107595 Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis Díaz Gavilán, Mónica https://hdl.handle.net/10481/107595 https://hdl.handle.net/10481/107504 A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites Moya-Garzon, Maria Dolores; Wang, Mengjie; Li, Veronica L.; Lyu, Xuchao; Wei, Wei; Tung, Alan Sheng-Hwa; Raun, Steffen H.; Zhao, Meng; Coassolo, Laetitia; Islam, Hashim; Oliveira, Barbara; Dai, Yuqin; Spaas, Jan; Delgado-Gonzalez, Antonio; Donoso, Kenyi; Alvarez-Buylla, Aurora; Franco-Montalban, Francisco; Anudari, Anudari; Ward, Catherine P.; Liu, Lichao; Svensson, Katrin J.; Goldberg, Emily L.; Gardner, Christopher D.; Little, Jonathan P.; Banik, Steven M.; Xu, Yong; Long, Jonathan Z. β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance. https://hdl.handle.net/10481/107504