352 research outputs found
Influence of allosteric Hsp90 ATPase activators on its chaperoning activity
No full textHsp90 is a molecular chaperone with a starring role in the cell life cycle1 and an established anti-apoptotic target in cancer therapy.2 The protein internal dynamics are regulated by ATP and are critical for its function. Hsp90 can be modulated in an allosteric fashion as we have recently demonstrated, targeting the protein C-terminal domain (CTD) with a family of 2-phenyl-benzofuran derivatives.3-5 These compounds accelerate Hsp90 internal dynamics and increase its enzymatic ATPase activity. As a result, they tune its chaperone activity in ways that we are just beginning to unravel.
The synthetic approaches towards an expanded library of about 40 benzofuran derivatives will be presented. The interaction studies with full length Hsp90,6 and the effects on Hsp90 enzymatic and chaperoning activity will be reported for selected compounds.
References
1. S. E. Jackson In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg (2013) Vol. 328, p 155-240.
2. J. Trepel, M. Mollapour, G. Giaccone, and L. Neckers Nat Rev Cancer (2010), 10, 537-549.
3. L. Morelli, A. Bernardi and S. Sattin, Carbohydr. Res. (2014), 390, 33-41.
4. S. Sattin et al Chem. Eur. J. (2015), 21, 13598-13608.
5. G. Vettoretti, E. Moroni, S. Sattin, J. Tao, D.A. Agard, A. Bernardi and G. Colombo Sci Rep (2016), 6, 23830.
6. S. Sattin, M. Panza, F. Vasile, F. Berni, G. Goti, J. Tao, E. Moroni, D.A. Agard, G. Colombo and A. Bernardi
Eur. J.Org. Chem. (2016) DOI: 10.1002/ejoc.201600420
Synthesis and characterization of Hsp90 allosteric activators
No full textHsp90 is a molecular chaperone playing a pivotal role in the cell life cycle1 and an established anti-apoptotic target in cancer therapy.2 The protein internal dynamics are regulated by ATP and are critical for its function. We have recently demonstrated that Hsp90 can be modulated in an allosteric fashion, targeting the protein C-terminal domain (CTD) with a family of 2-phenyl-benzofuran derivatives.3-5 These molecules increase Hsp90 ATPase rate and accelerate its internal dynamics. As a result they tune its chaperone activity in ways that we are just beginning to unravel.
The synthetic approaches towards an expanded library of about 40 benzofuran derivatives diversified at positions R1 and R2 (Figure 1) will be presented together with the interaction studies with full length Hsp90.6
Figure 1: 2-phenyl-benzofuran diversification at positions R1 and R2.
1) Jackson, S. E. In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg: 2013; Vol. 328, p 155-240.
2) Trepel, J.; Mollapour, M.; Giaccone, G. and Neckers, L., Nat Rev Cancer 2010, 10, 537-549.
3) Morelli, L.; Bernardi, A. and Sattin, S.*, Carbohydr. Res. 2014, 390, 33-41.
4) Sattin, S. et al Chem. Eur. J. 2015, 21, 13598-13608.
5) Vettoretti, G; Moroni, E.; Sattin, S.; Tao, J.; Agard, D. A.;. Bernardi, A. and Colombo, G. Sci Rep 2016, 6, 23830.
6) Sattin, S.*; Panza, M.; Vasile, F.; Berni, F.; Goti, G.; Tao, J.; Moroni, E.; Agard, D.; Colombo, G. and Bernardi, A. Eur. J.Org. Chem. 2016 DOI: 10.1002/ejoc.201600420
Benzofuran Derivatives Activators of the Chaperone Protein Hsp90: Synthesis, Interaction Studies and Biological Effects
No full textWe have recently reported that allosteric modulation of the chaperone protein Hsp901 can be achieved in an allosteric fashion using a family of 2-phenyl-benzofuran derivatives that target an allosteric pocket at the C-terminal domain of the protein.2,3 These ligands are mainly activators of the chaperone ATPase activity3 and are accelerators of the protein internal dynamics.4 As a result, they tune Hsp90 chaperone activity in ways that we are just beginning to unravel.
We are going to present the synthetic approaches towards an expanded library of about 40 benzofuran derivatives diversified at positions R1 and R2 along with the interaction studies with full length Hsp905 and the effects on Hsp90 enzymatic and chaperoning activity.
Figure 1: 2-phenyl-benzofuran diversification at positions R1 and R2 (top) and docked complex of Hsc82 (Hsp90 yeast form) with one of our derivatives (bottom).
1. Jackson, S. E. In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg: 2013; Vol. 328, p 155.
2. Morelli, L.; Bernardi, A.; Sattin, S. Carbohydr Res 2014, 390C, 33.
3. Sattin, S.; Tao, J.; Vettoretti, G.; Moroni, E.; Pennati, M.; Lopergolo, A.; Morelli, L.; Bugatti, A.; Zuehlke, A.; Moses, M.; Prince, T.; Kijima, T.; Beebe, K.; Rusnati, M.; Neckers, L.; Zaffaroni, N.; Agard, D. A.; Bernardi, A.; Colombo, G. Chem. Eur. J. 2015, 21, 13598.
4. Vettoretti, G.; Moroni, E.; Sattin, S.; Tao, J.; Agard, D. A.; Bernardi, A.; Colombo, G. Sci Rep 2016, 6, 23830.
5. Sattin, S.; Panza, M.; Vasile, F.; Berni, F.; Goti, G.; Tao, J.; Moroni, E.; Agard, D.; Colombo, G.; Bernardi, A. Eur. J. Org. Chem. 2016, DOI: 10.1002/ejoc.201600420
Allosteric modulators of Hsp90: design, synthesis and activity evaluation
No full textHsp90 is a molecular chaperone playing a pivotal role in the cell life cycle, an established anti-apoptotic target in cancer therapy[1] and a promising target for neurodegenerative diseases.[2] Hsp90 internal dynamics, crucial for its function, are strongly ATP-regulated and current pharmacological approaches block the chaperone with ATP-competitive inhibitors, inducing non-negligible secondary effects.
We recently demonstrated that the protein internal dynamics can be modulated, and in particular activated, in an allosteric fashion, targeting the protein C-terminal domain (CTD) with a family of 2-phenyl-benzofuran derivatives.[3,4] The allosteric site we recently identified[5] is mechanically connected to the distal orthosteric ATP-binding site (65 Å) and the small variations induced by binding of the majority of our allosteric modulators produce significant variations of the protein overall dynamics, which translate macroscopically into an acceleration of the chaperone ATPase rate. Analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis and protein closure kinetics.[6]
The expansion of the initial library with 28 new derivatives that explore the chemical space at opposite ends of the benzofuran scaffold will be described. Their interaction with the full-length protein by STD-NMR and their effect on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties will be also presented.
Figure 1: A) Structure of a representative allosteric modulator and B) its docked conformation within the allosteric site.
References
1) Trepel, J.; Mollapour, M.; Giaccone, G.et al, Nat Rev Cancer 2010, 10, 537-549.
2) Uversky, V. N., Chem. Rev. 2010, 111, 1134-1166.
3) Morelli, L.; Bernardi, A. and Sattin, S., Carbohydr Res 2014, 390C, 33-41.
4) Sattin, S.; Tao, J.; Vettoretti, G.et al, Chem. Eur. J. 2015, 21, 13598-13608.
5) Morra, G.; Neves, M. A. C.; Plescia, C. J.et al, J. Chem. Theory Comput. 2010, 6, 2978-2989.
6) Vettoretti, G.; Moroni, E.; Sattin, S.et al, Sci Rep 2016, accepted DOI: 10.1038/srep23830
Collisionless sound of bosonic superfluids in lower dimensions
No full textThe superfluidity of low-temperature bosons is well established in the collisional regime. In the collisionless regime, however, the presence of superfluidity is not yet fully clarified, in particular in lower spatial dimensions. Here, we compare the Vlasov-Landau equation, which does not take into account the superfluid nature of the bosonic system, with the Andreev-Khalatnikov equations, which instead explicitly contain a superfluid velocity. We show that recent experimental data of the sound mode in a two-dimensional collisionless Bose gas of Rb87 atoms are in good agreement with both theories, but the sound damping is better reproduced by the Andreev-Khalatnikov equations below the Berezinskii-Kosterlitz-Thouless critical temperature Tc, while above Tc the Vlasov-Landau results are closer to the experimental ones. For one-dimensional bosonic fluids, where experimental data are not yet available, we find larger differences between the sound velocities predicted by the two transport theories and, also in this case, the existence of a superfluid velocity reduces the sound damping
On the convergence of the WKB series for the angular momentum operator
No full textIn this paper we prove a recent conjecture about the convergence of the WKB series for the angular momentum operator. We demonstrate that the WKB algorithm for the angular momentum gives the exact quantization formula if all orders are summed. Finally, we discuss the supersymmetric semiclassical quantum mechanics (SWKB), which gives the correct quantization of the angular momentum at the leading order
SWKB for the angular momentum
No full textIt has been recently shown [M. Robnik and L. Salasnich, J. Phys. A: Math. Gen. 30, 1719 (1997)] that the WKB series for the quantization of angular momentum L converges to the exact value L-2 = (h) over bar(2)l(l + 1), if summed over all orders, and gives the Langer formula L-2 = (h) over bar 2(l + 1/2)(2) at the leading order. In this work we solve the eigenvalue problem of the angular momentum operator by using the supersymmetric semiclassical quantum mechanics (SWKB), and show that it gives the correct quantization already at the leading order
Multiparameter generalization of nonextensive statistical mechanics
No full textWe show that the stochastic interpretation of Tsallis's thermostatistics given recently by Beck [Phys. Rev. Lett 87, 180601 (2001)] leads naturally to a multiparameter generalization. The resulting class of distributions is able to fit experimental results, which cannot be reproduced within Boltzmann's or Tsallis's formalism
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