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Marcos-Ramiro B, Gil-Ordóñez A, Marín-Ramos NI, et al. Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome. ACS Cent Sci. 2021;7(8):1300-1310doi: 10.1021/acscentsci.0c01698.
Marcos-Ramiro, B., Gil-Ordóñez, A., Marín-Ramos, N. I., Ortega-Nogales, F. J., Balabasquer, M., Gonzalo, P., Khiar-Fernández, N., Rolas, L., Barkaway, A., Nourshargh, S., Andrés, V., Martín-Fontecha, M., López-Rodríguez, M. L., & Ortega-Gutiérrez, S. (2021). Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome. ACS central science, 7(8), 1300-1310. https://doi.org/10.1021/acscentsci.0c01698
Marcos-Ramiro, Beatriz, et al. "Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome." ACS central science vol. 7,8 (2021): 1300-1310. doi: https://doi.org/10.1021/acscentsci.0c01698
Marcos-Ramiro B, Gil-Ordóñez A, Marín-Ramos NI, Ortega-Nogales FJ, Balabasquer M, Gonzalo P, Khiar-Fernández N, Rolas L, Barkaway A, Nourshargh S, Andrés V, Martín-Fontecha M, López-Rodríguez ML, Ortega-Gutiérrez S. Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome. ACS Cent Sci. 2021 Aug 25;7(8):1300-1310. doi: 10.1021/acscentsci.0c01698. Epub 2021 Jun 27. PMID: 34471675; PMCID: PMC8393201.
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ACS Cent Sci. 2021 Aug 25;7(8):1300-1310. doi: 10.1021/acscentsci.0c01698. Epub 2021 Jun 27.

Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome.

ACS central science

Beatriz Marcos-Ramiro, Ana Gil-Ordóñez, Nagore I Marín-Ramos, Francisco J Ortega-Nogales, Moisés Balabasquer, Pilar Gonzalo, Nora Khiar-Fernández, Loïc Rolas, Anna Barkaway, Sussan Nourshargh, Vicente Andrés, Mar Martín-Fontecha, María L López-Rodríguez, Silvia Ortega-Gutiérrez

Affiliations

  1. Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
  2. CEI Campus Moncloa, UCM-UPM and CSIC, E-28040 Madrid, Spain.
  3. Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
  4. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain.
  5. Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom.

PMID: 34471675 PMCID: PMC8393201 DOI: 10.1021/acscentsci.0c01698

Abstract

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the

© 2021 The Authors. Published by American Chemical Society.

Conflict of interest statement

The authors declare no competing financial interest.

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