Synthetic routes to NEtXaa4-cyclosporin A derivatives as potential anti-HIV I drugs

Hubler, Francis; Rückle, Thomas; Patiny, Luc; Tshilolo, Muamba; Guichou, Jean-François; Mutter, Manfred; Wenger, Roland M.

doi:10.1016/s0040-4039(00)01267-3

Cited by 35 publications

(37 citation statements)

References 21 publications

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“…Although in agreement with previous functional studies that showed consistently a lower IC 50 value for both compounds as compared to CsA, 7,8 this …”

supporting

confidence: 94%

Ranking High Affinity Ligands of Low Solubility by NMR Spectroscopy

Landrieu

Hanoulle

Fritzinger

et al. 2011

ACS Med. Chem. Lett.

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C ommon wisdom holds that the experimental measurement of ligand/receptor binding parameters requires concentrations of both partners of the order of the dissociation constant (K D ) to be determined. Whereas this puts NMR spectroscopy in a favorable position to determine the interaction parameters for many biologically relevant molecular interactions, pharmacological ligands often have K D values in the nanomolar range. Fluorescence spectroscopy with its superior sensitivity seems better suited to characterize such ligands but does require fluorescence of the ligand or the receptor to change upon interaction. Low solubility in water is another recurrent issue when characterizing the binding properties of pharmacological ligands, whereby the addition of inorganic solvent and their effect on the protein and protein binding have to be carefully controlled.Within a given series of (un)related ligands, one typically looks for a relative ranking of the molecules and potentially for information on the identity of the binding site. Competition experiments are the most obvious choice for such a ranking. We propose here the use of NMR spectroscopy in a competition experiment that gives simultaneous relative K D values for the ligands and also qualitative information on the binding site. We demonstrate the method by ranking the binding of the N-methyl D-Ala3/N-ethyl Val4 cyclosporin A (named Alisporivir) toward the human cyclophilin A (CypA) as compared to its mother compound cyclosporin A (CsA) and two chemical intermediates, the N-ethyl Val4 Cs (EthV4Cs) and the N-methyl Val4 Cs (MeV4Cs). Alisporivir is a nonimmunosuppressive analogue of CsA ( Figure S1 in the Supporting Information) that presents better antiviral properties than CsA inhibiting HCV subgenomic replicon replication.1,2 Ranking the ligands for CypA binding might help to establish whether differential affinity can explain the biological observation of Alisporivir's superior antiviral character.When complexing the protein with one or the other ligand, we had previously noticed 3 that the differential chemical shift changes, that is, between CypAÀCsA and CypAÀAlisporivir, were very limited and localized but clearly could be observed for a couple of resonance peaks (Figure 1 and Figure A 1:1 CsA:Alisporivir mixture from individual 5 mg/mL stock solutions in chloroform of both undecapeptides was directly deposited in a standard NMR tube. The chloroform was evaporated under nitrogen flux, leaving a white solid layer containing both ligands at the glass interface.15 N-labeled CypA protein solution was introduced in this tube, and sequential [ 1 H, 15 N]-HSQC spectra were recorded. Whereas the resonances corresponding to the free CypA protein were initially the only ones detected, novel resonances that had been assigned to both CypA complexes 3 gradually appeared (Figure 1). Integration of these peaks in a series of HSQC spectra showed a linear decrease of the free CypA peaks, reflecting the complete loading of the protein with the ligands. Peak integrals corresp...

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“…Although in agreement with previous functional studies that showed consistently a lower IC 50 value for both compounds as compared to CsA, 7,8 this …”

supporting

confidence: 94%

Ranking High Affinity Ligands of Low Solubility by NMR Spectroscopy

Landrieu

Hanoulle

Fritzinger

et al. 2011

ACS Med. Chem. Lett.

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“…The preparation of Debio 025 was based on the strategy used for the synthesis of D-methyl-Ala 3 -ethyl-Xaa 4 -cyclosporine analogues described previously (24). Cs was purchased from Fluka Chemie GmbH (Buchs, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Debio 025, a Cyclophilin Binding Molecule, Is Highly Efficient in Clearing Hepatitis C Virus (HCV) Replicon-Containing Cells When Used Alone or in Combination with Specifically Targeted Antiviral Therapy for HCV (STAT-C) Inhibitors

Coelmont

Kaptein

Paeshuyse

et al. 2009

Antimicrob Agents Chemother

121

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Hepatitis C virus (HCV) represents a major health burden. An estimated 170 million to 180 million people worldwide are chronically infected with this virus and are at increased risk of developing liver cirrhosis and/or hepatocellular carcinoma (64). The current standard of care for chronic hepatitis C consists of pegylated alpha interferon (IFN) in combination with ribavirin (RBV) (12). This therapy is, however, associated with serious side effects and results in a sustained virological response in only 50 to 60% of patients (depending on the genotype). There is thus an urgent need for more effective and better-tolerated drugs.Selective inhibitors of HCV replication that target the NS3 protease and the NS5B RNA-dependent RNA polymerase (RdRp) in particular have been pursued as potential new therapies (38). BILN 2061 (culprivir), a peptidomimetic inhibitor of the HCV NS3 protease (the first selective inhibitor of HCV to be administered to patients), resulted in a rapid and pronounced decline in the level of viral replication in patients chronically infected with HCV genotype 1. Its clinical development was, however, halted because of cardiotoxicity (22,31). Currently, four NS3 protease inhibitors are in clinical development, i.e., VX-950 (telaprevir), SCH-503034 (boceprevir), and TMC435350 (2,51,56). Telaprevir and boceprevir are at the most advanced stages of development and are being evaluated in combination with the standard therapy in phase III and phase II clinical trials, respectively (3,39,45,50). Several nucleoside polymerase inhibitors (NIs) and nonnucleoside polymerase inhibitors (NNIs) are or have been in development. Nucleoside analogue inhibitors of HCV replication basically act as chain terminators of the polymerization process once they have been phosphorylated to their 5Ј-triphosphate metabolite (13).

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“…The preparation of DEBIO-025 was based on the synthetic strategy for D-MeAla 3 -EtXaa 4 -cyclosporin analogs described previously. 23 CsA was purchased from Fluka Chemie GmbH (9471 Buchs, Switzerland), 2Ј-C-methyl-Cytidine, 24 25 and VX-950 [26][27][28] were synthesized by standard methods.…”

Section: Methodsmentioning

confidence: 99%