X-ray structure of alisporivir in complex with cyclophilin A at 1.5 Å resolution

Dujardin, Marie; Bouckaert, Julie; Rucktooa, Prakash; Hanoulle, Xavier

doi:10.1107/s2053230x18010415

Cited by 7 publications

(10 citation statements)

References 48 publications

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“…Cyclosporin(e) A (CycA, Figure A), an 11-amino-acid lipophilic macrocyclic drug from Tolypocladium inflatum , has revolutionized transplant medicine due to its immunosuppressive property. − The cyclosporin–cyclophilin complex inhibits calcineurin normally involved in T-cell activation. , The biological applications of cyclosporines are not limited to immunosuppression; nonimmunosuppressive analogues such as alisporivir (Figure S1), , have been developed to no longer inhibit calcineurin, yielding potent cyclophilin inhibitors that target virus replication. − …”

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“…For CycH, the all- trans conformer does not improve interactions with CypA. ,, Interestingly, both CycA and CycG adopt A1 and have similar biological activities. − We observe that the analogues lose activity when the structural modifications perturb MeBmt1 or MeVal11, i.e., MeBmt1→MeLeu1 in CycO (less bulky) and ( l )→( d )-MeVal in CycH (steric). Such modifications are not found in analogues with strong CypA affinities (e.g., alisporivir, NIM811, voclosporine).…”

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confidence: 99%

“…1−3 The cyclosporin−cyclophilin complex inhibits calcineurin normally involved in T-cell activation. 4,5 The biological applications of cyclosporines are not limited to immunosuppression; nonimmunosuppressive analogues such as alisporivir (Figure S1), 6,7 have been developed to no longer inhibit calcineurin, yielding potent cyclophilin inhibitors that target virus replication. 6−9 It has been four decades since CycA came into medical use.…”

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Atomic View of Aqueous Cyclosporine A: Unpacking a Decades-Old Mystery

et al. 2022

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An atomic view of a main aqueous conformation of cyclosporine A (CycA), an important 11-amino-acid macrocyclic immunosuppressant, is reported. For decades, it has been a grand challenge to determine the conformation of free CycA in an aqueous-like solution given its poor water solubility. Using a combination of X-ray and single-crystal neutron diffraction, we unambiguously resolve a unique conformer (A1) with a novel cis-amide between residues 11 and 1 and two water ligands that stabilize hydrogen bond networks. NMR spectroscopy and titration experiments indicate that the novel conformer is as abundant as the closed conformer in 90/10 (v/v) methanol/water and is the main conformer at 10/90 methanol/water. Five other conformers were also detected in 90/10 methanol/water, one in slow exchange with A1, another one in slow exchange with the closed form and three minor ones, one of which contains two cis amides Abu2−Sar3 and MeBmt1−MeVal11. These conformers help better understand the wide spectrum of membrane permeability observed for CycA analogues and, to some extent, the binding of CycA to protein targets.

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Atomic View of Aqueous Cyclosporine A: Unpacking a Decades-Old Mystery

et al. 2022

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“…In particular, we chose to work with CycA , Alisporivir ( ALI ), and cyclosporine H ( CycH ). ALI is a synthetic nonimmunosuppressant analogue, developed by Debiopharm, that has comparable membrane permeability to CycA and also binds strongly to CypA. , ALI was strategically designed for differing from CycA at only two residues, d -MeAla3 and EtVal4, so it does not bind calcineurin. ,, ALI is currently being researched for potential use in treating hepatitis C ,, and SARS-CoV-2 . The second analogue, CycH, is a CycA epimer with a d -MeVal11.…”

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Taming Conformational Heterogeneity on Ion Racetrack to Unveil Principles that Drive Membrane Permeation of Cyclosporines

Limbach,

Lindberg,

Olivos

et al. 2024

JACS Au

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Our study reveals the underlying principles governing the passive membrane permeability in three large N-methylated macrocyclic peptides (N-MeMPs): cyclosporine A (CycA), Alisporivir (ALI), and cyclosporine H (CycH). We determine a series of conformers required for robust passive membrane diffusion and those relevant to other functions, such as binding to protein targets or intermediates, in the presence of solvent additives. We investigate the conformational interconversions and establish correlations with the membrane permeability. Nuclear magnetic resonance (NMR) and cyclic ion-mobility spectrometry-mass spectrometry (cIMS-MS) are employed to characterize conformational heterogeneity and identify cis-amides relevant for good membrane permeability. In addition, ion mobility selected cIMS-MS and infrared (IR) multiple-photon dissociation (IRMPD) spectroscopy experiments are conducted to evaluate the energy barriers between conformations. We observe that CycA and ALI, both cyclosporines with favorable membrane permeabilities, display multiple stable and well-defined conformers. In contrast, CycH, an epimer of CycA with limited permeability, exhibits fewer and fewer stable conformers. We demonstrate the essential role of the conformational shift from the aqueous cis MeVal11−MeBmt1 state (A1) to the closed conformation featuring cis MeLeu9−MeLeu10 (C1) in facilitating membrane permeation. Additionally, we highlight that the transition from A1 to the all-trans open conformation (O1) is specifically triggered by the presence of CaCl 2 . We also capture a set of conformers with cis Sar3−MeLeu4, MeLeu9−MeLeu10, denoted as I. Conformationally selected cIMS-MS and IRMPD data of [CycA+Ca] 2+ show immediate repopulation of the original population distribution, suggesting that CaCl 2 smooths out the energy barriers. Finally, our work presents an improved sampling molecular dynamics approach based on a refined force field that not only consistently and accurately captures established conformers of cyclosporines but also exhibits strong predictive capabilities for novel conformers.

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“…This suggests that SARS-CoV-2 regulates the NFAT pathway via CypA–Nsp1 interaction for inhibiting cytokine production. Earlier studies in MERS infection showed that small molecule drugs cyclosporin A and alisporivir restrict MERS-CoV infection. , Although the mechanism of alisporivir binding to CypA is similar to that of cyclosporinA (PDB: 5HSV), the molecular details of how alisporivir and cyclosporin restrict viral infection remain elusive. Furthermore, previous clinical studies have shown that CypA is required for the IFN-inducible MX2-mediated antiviral activity and also demonstrated that CypA-regulated ubiquitination is critical for antiviral immune response in infected mice .…”

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confidence: 99%