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Volume 16
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10.3390/ph16040616
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Article

Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications

by
Nuria Vilaboa
1,2,*,
Juan Antonio Lopez
3,4,
Marco de Mesa
1,
Clara Escudero-Duch
1,2,
Natalie Winfield
5,
Melanie Bayford
5 and
Richard Voellmy
6,*
1
Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain
2
CIBER de Bioingenieria, Biomateriales y Nanomedicina, CIBER-BBN, 28046 Madrid, Spain
3
Centro Nacional de Investigaciones Cardiovasculares, CNIC, 28029 Madrid, Spain
4
CIBER de Enfermedades Cardiovasculares, CIBERCV, 28029 Madrid, Spain
5
Domainex Ltd., Chesterford Research Park, Little Chesterford, Essex, Saffron Walden CB10 1XL, UK
6
HSF Pharmaceuticals SA, 1814 La Tour-de-Peilz, Switzerland
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2023, 16(4), 616; https://doi.org/10.3390/ph16040616
Submission received: 22 February 2023 / Revised: 11 April 2023 / Accepted: 17 April 2023 / Published: 19 April 2023
(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)
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Abstract

Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells revealed that withaferin A, IHSF058 and IHSF115 caused denaturation of 915, 722 and 991 of 5132 detected cellular proteins, respectively, of which 440 were targeted by all three compounds. Western blots showed that important fractions of these proteins, in some cases approaching half of total protein amounts, unfolded. Relatively indiscriminate covalent modification of target proteins was observed; 1178 different proteins were modified by IHSF058. Further illustrating the depth of the induced proteostasis crisis, only 13% of these proteins detectably aggregated, and 79% of the proteins that aggregated were not targets of covalent modification. Numerous proteostasis network components were modified and/or found in aggregates. Proteostasis disruption caused by the study compounds may be more profound than that mediated by proteasome inhibitors. The compounds act by a different mechanism that may be less susceptible to resistance development. Multiple myeloma cells were particularly sensitive to the compounds. Development of an additional proteostasis-disrupting therapy of multiple myeloma is suggested.
Keywords: proteostasis inhibition; proteostasis disruption; protein unfolding; protein aggregation; IHSF; celastrol; withaferin A; multiple myeloma 1 proteostasis inhibition; proteostasis disruption; protein unfolding; protein aggregation; IHSF; celastrol; withaferin A; multiple myeloma 1

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MDPI and ACS Style

Vilaboa, N.; Lopez, J.A.; de Mesa, M.; Escudero-Duch, C.; Winfield, N.; Bayford, M.; Voellmy, R. Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications. Pharmaceuticals 2023, 16, 616. https://doi.org/10.3390/ph16040616

AMA Style

Vilaboa N, Lopez JA, de Mesa M, Escudero-Duch C, Winfield N, Bayford M, Voellmy R. Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications. Pharmaceuticals. 2023; 16(4):616. https://doi.org/10.3390/ph16040616

Chicago/Turabian Style

Vilaboa, Nuria, Juan Antonio Lopez, Marco de Mesa, Clara Escudero-Duch, Natalie Winfield, Melanie Bayford, and Richard Voellmy. 2023. "Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications" Pharmaceuticals 16, no. 4: 616. https://doi.org/10.3390/ph16040616

APA Style

Vilaboa, N., Lopez, J. A., de Mesa, M., Escudero-Duch, C., Winfield, N., Bayford, M., & Voellmy, R. (2023). Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications. Pharmaceuticals, 16(4), 616. https://doi.org/10.3390/ph16040616

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