ODU Digital ODU Digital HSP90 Inhibitors for IPF/COVID-19 HSP90 Inhibitors for IPF/COVID-19

Heat shock protein 90 (HSP90) is an important chaperone that assists the late stage folding of several proteins involved in cell survival in response to environmental stressors. The inhibition of HSP90 is followed by a complex modulation of the proteome and the kinome, that has proved beneficial in cancer and various neurodegenerative diseases. Additionally, accumulating literature suggests that HSP90 may be a key target during the development of pulmonary fibrosis and that its inhibition could serve as a new and exciting therapeutic approach. We have summarized the current evidence about HSP90’s role in Idiopathic Pulmonary Fibrosis (IPF), the results from preclinical studies on its inhibition and the intracellular signaling pathways involved, in a recent review article (Review). In this Article entry, we will introduce the main findings discussed in the review and focus on its translation and possible significance in the era of the SARS-CoV-2 pandemic.


Definition
HSP90 is a highly expressed and conserved chaperone, described in diverse isoforms (e.g. α, β, mitochondrial), whose activity is necessary for the proper folding of many client proteins. Different isoform of HSP90 can assemble in heterogeneous or homologous dimers (HSP90αα, HSP90ββ or HSP90αβ), with specific chaperone profiles and affinity for protein partners . Few studies have characterized both α and β isoforms behavior during the fibrotic process. HSP90β has shown specific tubulin and microtubule-interacting properties playing a role in cell motility, migration and structural cell stability .
HSP90α expression is modulated by Signal Transducer and Activator of Transcription 1 (STAT1) and is involved in cell survival by modulating the caspase 3-depending apoptotic pathway . However, more data is required for a better understanding of HSP90 isoforms, especially in order to develop inhibitors with lower or higher affinity.
Fibroblasts represent the central mediators of the fibrotic process as they promote cellular proliferation and deposition of extracellular matrix (ECM) in response to prolonged tissue injury and chronic inflammation . Transforming growth factor-β (TGF-β) is the most important mediator of fibrogenesis, which upregulates and activates fibroblast phenotype and function, inducing fibroblast transdifferentiation . TGF-β signaling is mediated by a complex subset of intracellular mediators divided into the non-Smad-and Smad-dependent signaling pathways . HSP90 stabilizes the TGF-β receptor, modulates its signaling cascades and, similarly to TGF-β, directs myofibroblast differentiation.
Samples taken from patients with IPF revealed the presence of both HSP90α and HSP90β in the pulmonary interstitial tissue, whose expression was increased in areas rich in myofibroblasts and fibroblasts . These fibroblasts localized HSP90 mainly in the nucleus and cytosol, and when treated with HSP90 inhibitors, displayed impaired proliferation, migration and differentiation . Indeed, HSP90 administration increased Heat shock protein 90 (HSP90) is an important chaperone that assists the late stage folding of several proteins involved in cell survival in response to environmental stressors. The inhibition of HSP90 is followed by a complex modulation of the proteome and the kinome, that has proved beneficial in cancer and various neurodegenerative diseases. Additionally, accumulating literature suggests that HSP90 may be a key target during the development of pulmonary fibrosis and that its inhibition could serve as a new and exciting therapeutic approach. We have summarized the current evidence about HSP90's role in Idiopathic Pulmonary Fibrosis (IPF), the results from preclinical studies on its inhibition and the intracellular signaling pathways involved, in a recent review article (Review). In this Article entry, we will introduce the main findings discussed in the review and focus on its translation and possible significance in the era of the SARS-CoV-2 pandemic. 2. HSP90 directs myofibroblast differentiation [7] [8] [9][10] [3] [11] [4] Proteomic profiling plays an important role in biomarker discovery. Proteomic analyses in IPF have been done on peripheral blood, bronchoalveolar lavage fluid (BALF) and lung tissue. While HSP90β-1 was found increased in peripheral blood of patients with IPF , both HSP90α and HSP90β were found increased in lung tissue . HSP90 exerts distinct roles when expressed intracellularly, intranuclearly or released into the vascular compartment. Indeed, intracellular HSP90 acts as a chaperone, assisting the maturation, correcting the folding and when irreversibly damaged, promoting the degradation of several client proteins . Differently, HSP90 can be released extracellularly in conditions of stress, promoting Antigen Presenting Cells (APC) maturation and, acting as "alarmins", triggers the immune system response .
Thus, IPF displays high levels of HSP90 both intra-and extra-cellularly, which are required for both the augmented intracellular signaling -and subsequent elevated chaperone activity-and for the activation of the immune system in response to the chronic inflammation in the lung.
HSP90 inhibitors modulate and reduce protein trafficking, restore proteostasis and diminish HSP90 chaperone activity, thus blocking the fibrotic process . The number of HSP90 inhibitors has dramatically increased since the first molecule described in 1994 . Geldanamycin is a natural product and a member of the benzoquinone annamycin family that has demonstrated anti-tumor and anti-proliferative characteristics, whose clinical implementation, however, was limited due to liver toxicity . 17-N-  and reducing the production of pro-fibrotic mediators and ECM. HSP90 inhibitors then, modulating the "HSPome", not only block the crucial intracellular signaling of TGF-β, but also modulate the inflammatory markers (via extracellular HSP90) related to IPF. Figure 1. Schematic representation of HSP90 involvement in TGF-β signaling cascade. HSP90 plays a crucial role at various levels of the pathogenic pathway of IPF. It stabilizes TGF-β receptor, negatively [27] 5. HSP90 inhibition modulates the fibrotic process [28] [29][30] [31] [25] [27] [32] [23] [33] [34] regulates Raf, preserve ERK from degradation with its binding with HSP90-CDC37 complex and modulates nuclear localization of phospho-Smad4. In this Article Entry we briefly introduced the most significant results of HSP90 inhibition and modulation of the Proteome as potential therapies against the development of pulmonary fibrosis. We then translated their significance to the era of the SARS-CoV-2 pandemic.