Isoform-Specific Inhibition of Cyclophilins

Daum, Sebastian; Schümann, Michael; Mathea, Sebastian; Aumüller, Tobias; Balsley, Molly A.; Constant, Stephanie L.; Lacroix, Boris Féaux de; Kruska, Fabian; Braun, Manfred; Schiene‐Fischer, Cordelia

doi:10.1021/bi9007287

Cited by 67 publications

(89 citation statements)

References 69 publications

(139 reference statements)

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“…Our FEP/MC simulations have indicated that 2 takes advantage of these subtle differences via different binding motifs that fine-tune their selectivity for CypA by exclusively weakening their nonbonded interactions with the catalytic Arg63 and Asn110 residues in CypB. Relative free energies of binding, ΔΔG bind , given in Table 2 for the 2a-2c inhibitors were computed in both CypA and CypB using the MC/FEP transformation sequence given in Figure 9 and were found to yield excellent agreement with the experimental free-energy differences derived from the K i protease-free PPIase assay at pH 7.8 and 283K [113,189]. Figure 10 shows two binding modes for 2a in the overlaid CypA and CypB active sites where the lighter colored structure is the preferred binding conformation in CypA and the darker structure is favored in CypB.…”

Section: Selectivity Towards Cypamentioning

confidence: 71%

“…This isomerization has been identified as the rate-limiting step in protein folding [106,107]. Review of the biochemistry of the PPIases is well-represented in the literature with an emphasis on overall biological relevance [108,109], foundational biochemistry [110,111], mechanism [112], inhibitors [113][114][115][116], and possible therapeutic utility [117]. Eight human Cyps with molecular masses ranging from 18 to 150 kDa [107] and an additional 12 multidomain Cyps (masses up to 352 kDa) have been reported that contain a highly conserved active site, making specific inhibition of a particular family member difficult [118].…”

Section: Cyclophilinsmentioning

confidence: 99%

“…It has only been shown recently that small molecules can differentiate between isoforms of cyclophilins, particularly CypA and CypB. These results have emanated primarily from the laboratories of Fisher [113,183,184] and Li [185][186][187]. Recent structural analysis of known human cyclophilins utilizing both X-ray crystal structures and homology modeling assuming an invariant Arg (Arg55 and Arg63 for CypA and CypB, respectively) have identified two specific locations near the catalytic site likely to confer isoform selectivity: the S2 pocket and the S1′ pocket.…”

Section: Small Molecule Inhibitors Of Cyp A/bmentioning

confidence: 99%

“…Our recent computational study utilizing FEP/MC simulations [189] elucidated the origin of the experimentally observed nanomolar inhibition of CypA by acylurea-based compounds, 1a-1j, featuring variations of R 1 and R 2 λ where the 2-Cl,6-F-phenyl ring derivative (1a) was the best reported inhibitor with an IC 50 of 2.6 nM for CypA inhibition. As a point of comparison CsA exhibits a 2.9 nM inhibition of CypA [113]. Table 1 provides the computed ΔΔG bind values with the correct binding affinity trend predicted when compared to the IC 50 enzyme inhibition assay results.…”

Section: Small Molecule Inhibitors Of Cyp A/bmentioning

confidence: 99%

“…Compound 2a (R 1 = NO 2 , R 2 = OH, and R 3 = NO 2 ) is particularly interesting because its K i value, as determined by a fluorescence quench assay, is reported to be 0.52 ± 0.15 μM in CypA and >100 μM in CypB implying a >200-fold selectivity between the cyclophilins from in vitro and in vivo experiments despite a completely conversed active site [113].…”

Section: Selectivity Towards Cypamentioning

confidence: 99%

See 4 more Smart Citations

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Acevedo¹,

Ambrose²,

Flaherty³

et al. 2012

curr drug metab

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Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.

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Section: Selectivity Towards Cypamentioning

confidence: 71%

Section: Cyclophilinsmentioning

confidence: 99%

Section: Small Molecule Inhibitors Of Cyp A/bmentioning

confidence: 99%

Section: Small Molecule Inhibitors Of Cyp A/bmentioning

confidence: 99%

Section: Selectivity Towards Cypamentioning

confidence: 99%

See 3 more Smart Citations

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Acevedo¹,

Ambrose²,

Flaherty³

et al. 2012

curr drug metab

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Peptidyl Prolylcis/transIsomerases

Schiene‐Fischer

2015

Encyclopedia of Life Sciences

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Peptidyl prolyl cis/trans isomerases (PPIases) are ubiquitous enzymes that catalyse the cis/trans isomerisation of peptide bonds preceding proline in peptides and proteins. PPIases can thus catalyse proline‐limited slow kinetic steps in the folding and rearrangement of proteins. Generally, by the regulation of the biological functions of their target proteins, PPIases are involved in the control of a wide variety of cellular processes, including transcription, cell proliferation, cell differentiation and apoptosis. They are implicated in many diseases such as cancer, inflammation, infection and neurodegeneration. PPIases comprise three families, the cyclophilins, the FK506‐binding proteins (FKBPs) and the parvulins, which are unrelated in their amino acid sequence and their three‐dimensional structure. Binding of cyclophilins and FKBP to their respective tight binding inhibitors, cyclosporin A and FK506, mediates the immunosuppressive action of these drugs by a gain‐of‐function mechanism. Key Concepts Peptidyl prolyl cis / trans isomerases catalyse the cis / trans isomerisation of peptide bonds preceding proline in peptides and proteins. The enzyme class of PPIases comprises three families, the cyclophilins, the FK506‐binding proteins (FKBPs) and the parvulins unrelated in their amino acid sequence and their three‐dimensional structure. The PPIase activity of members of the cyclophilin family is inhibited by the tight binding inhibitor cyclosporin A. The PPIase activity of members of the FKBP family is inhibited by FK506 and rapamycin. Members of the cyclophilin and FKBP families of PPIases are called immunophilins, because they mediate immunosuppression of the immunosuppressive drugs cyclosporin A, FK506 and rapamycin. Beside a role in protein folding, specific members of the three PPIase families perform specific tasks by the interaction with distinct substrate proteins in their native state, thereby regulating their functional properties.

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Nicht‐immunsuppressive Cyclophilin‐Inhibitoren

2022

Self Cite

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Cyclophiline, Enzyme mit einer Peptidyl-Prolyl-cis/trans-Isomerase-Aktivität, sind für eine Vielzahl biologischer Prozesse von Bedeutung. Das am häufigsten vorkommende Mitglied dieser Enzymfamilie, Cyclophilin A, ist der zelluläre Rezeptor des Immunsuppressivums Cyclosporin A (CsA). Aufgrund der pathophysiologischen Rolle der Cyclophiline, insbesondere bei Virusinfektionen, besteht ein breites Interesse an der Inhibierung von Cyclophilinen ohne immunsuppressive Wirkung. In diesem Überblick wird zunächst eine Einführung in die physiologische und pathophysiologische Rolle der Cyclophiline gegeben. Die Präsentation der nicht-immunsuppressiven Cyclophilin-Inhibitoren beginnt mit Wirkstoffen, die auf chemischen Modifikationen von CsA basieren. Die makrocyclischen, natürlich vorkommenden Sanglifehrine wurden zu einer weiteren Leitstruktur für Cyclophilin-inhibierende Wirkstoffe. Schließlich werden de novo entwickelte Verbindungen vorgestellt, deren Strukturen nicht von Naturstoffen abgeleitet oder durch sie inspiriert sind. Es werden relevante synthetische Konzepte erörtert, jedoch liegt auch ein Schwerpunkt auf biochemischen Untersuchungen, Struktur-Wirkungs-Beziehungen und klinischen Studien.

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Isoform-Specific Inhibition of Cyclophilins

Cited by 67 publications

References 69 publications

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Peptidyl Prolylcis/transIsomerases

Nicht‐immunsuppressive Cyclophilin‐Inhibitoren

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