Fine-Tuned Regulation of Hsp90: The New Frontier against Cancer and Neurodegeneration

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Background

Protein homeostasis is a delicate process necessary to safeguard cell physiological states and needs to be carefully regulated. In this scenario, the molecular chaperone HSP90 acts by promoting the correct folding of signaling proteins alongside stress response, the activation of clients in specific pathways, and by maintaining the non-toxic states of proteins which would be otherwise be particularly prone to aggregation. Thus, HSP90 is crucial in the onset and progression of different pathologies, such as cancer and neurodegeneration, in representing an attractive target for drug discovery.

HSP90 works as a homodimer and harbors two ATPase sites; indeed, the protein couples client maturation to ATP hydrolysis alongside a complex catalytic cycle regulated by large conformational changes of the chaperone. The growing amount of structural information appearing in recent years is helping to acquire a deeper knowledge on such an intricate system and has paved the road for the development of new drug-design strategies.

The HSP90 family of proteins is emerging as a valuable target in drug discovery due to its involvement in a plethora of cellular pathways. The first approach tested was the identification of analogues able to compete and bind the ATP-binding site to inhibit ATP hydrolysis and the subsequent client maturation. However, the ATP-binding site of HSP90 is conserved among different classes of proteins, i.e. the GHKL superfamily, and this strategy easily leads to off-targets. Moreover, cytoplasmic HSP90 and its organelle-specific isoforms TRAP1 and GRP94 are ubiquitous in all tissues and safeguard cell homeostasis. Thus, the modulation of the activity of these proteins needs to be finely regulated to avoid undesired side effects. To this aim, new drug-design strategies and protocols are being developed, taking advantage of combined experimental and theoretical pipelines.

These strategies include: i) identifying allosteric sites to be targeted by organic compounds able to modulate the activity of the chaperone; ii) identifying ligand binding sites that are unique to one isoform for targeting of cytoplasmic or organelle-specific isoforms; iii) disrupting the interaction of the chaperone with a specific client/co-chaperone by targeting protein-protein interfaces using peptide-based tools.

The aim of this Research Topic is to provide a collection of advances in the field of knowledge-based drug development targeting HSP90. The contributors are invited to submit research articles covering, but not limited to, the following themes:

• Deciphering the structural plasticity of HSP90 with an eye to drug discovery.
• Toward the development of isoform-specific ligands to avoid undesired side effects.
• The allosteric modulation of HSP90 as a promising strategy to avoid off-targets and cellular toxicity.
• Targeting protein-protein interfaces for the disruption of specific HSP90/client or HSP90/co-chaperone interaction. Inhibition of HSP90 along a specific and unique cellular pathway.

Topic editor Dr. Ilda D' Annessa is employed by Medtronic. All other Topic Editors declare no competing interests with regards to the Research Topic subject.

Keywords: HSP90 family, drug design, allosteric ligands, protein-protein interfaces, peptide-based tools, computer-aided drug design, structural biology, molecular dynamics

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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