Connecting the conformational behavior of cyclic octadepsipeptides with their ionophoric property and membrane permeability

Stadelmann, Thomas; Subramanian, Govindan; Menon, Sanjay; Townsend, Chad E.; Lokey, R. Scott; Ebert, Marc‐Olivier; Riniker, Sereina

doi:10.1039/d0ob01447h

Cited by 12 publications

(13 citation statements)

References 83 publications

(143 reference statements)

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“…Due to the high lipophilicity of the depsipeptides, incorporation into the membrane was hypothesized as a potential explanation for the apparent low permeability [ 15 ]. However, both cyclosporin A and emodepside are highly permeable in Caco-2 and MDCK-MDR1 cells, although they are only slightly less lipophilic compared with the other four depsipeptides ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to its poor in vitro permeability as reported in [15], emodepside is highly permeable in standard cellular permeability assays (Table 2). Surprisingly, for all four BI depsipeptides derived from modifications of the side-chains of emodepside, no meaningful permeability data could be obtained in MDCK-MDR1 and Caco-2 cells.…”

Section: In Vitro Permeability and Efflux Measured For Depsipeptides In Standard Assaysmentioning

confidence: 89%

“…With chemistry expanding into the bRo5 space in pharmaceutical research, standard in vitro ADME (absorption, distribution, metabolism, and excretion) assays often encounter difficulties in providing meaningful data to guide compound optimization, as exemplified here by our difficulties in measuring the permeability of cyclic depsipeptides. Different explanations have been proposed in the literature, such as incorporation into lipid bilayer [ 15 ], aggregation in aqueous solution [ 23 ], and compound loss due to nonspecific binding to the plasticware [ 25 ]. Our results here, however, did not agree with these explanations.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, permeability of emodepside was also demonstrated by brain distribution data; though its brain levels in wildtype (WT) mice were not detectable, emodepside showed comparable exposure in brain and plasma in P-gp deficient mice, indicating its permeability to the blood–brain barrier and the protective role of P-gp [ 14 ]. Despite these in vivo observations, in vitro measurement of permeability with emodepside was not successful [ 15 ]. In one of our antiparasitic programs for animal health, we identified some close analogs of emodepside with excellent efficacy against heartworm in dog.…”

Section: Introductionmentioning

confidence: 99%

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A Bidirectional Permeability Assay for beyond Rule of 5 Compounds

et al. 2021

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Bidirectional permeability measurement with cellular models grown on Transwell inserts is widely used in pharmaceutical research since it not only provides information about the passive permeability of a drug, but also about transport proteins involved in the active transport of drug substances across physiological barriers. With the increasing number of investigative drugs coming from chemical space beyond Lipinski’s Rule of 5, it becomes more and more challenging to provide meaningful data with the standard permeability assay. This is exemplified here by the difficulties we encountered with the cyclic depsipeptides emodepside and its close analogs with molecular weight beyond 1000 daltons and cLogP beyond 5. The aim of this study is to identify potential reasons for these challenges and modify the permeability assays accordingly. With the modified assay, intrinsic permeability and in vitro efflux of depsipeptides could be measured reliably. The improved correlation to in vivo bioavailability and tissue distribution data indicated the usefulness of the modified permeability assay for the in vitro screening of compounds beyond the Rule of 5.

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Section: Resultsmentioning

confidence: 99%

Section: In Vitro Permeability and Efflux Measured For Depsipeptides In Standard Assaysmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Bidirectional Permeability Assay for beyond Rule of 5 Compounds

et al. 2021

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“…A recent study demonstrated modulation of scaffold rigidity to engineer favorable ADME properties in macrocyclic peptides (Furukawa et al, 2020). Finally, drug design strategies, such as N-methylation or replacing NH with sulfur (or vice versa), were found to improve pharmacological activity, solubility, and/or permeability of macrocycles (Mallinson and Collins, 2012;Liras and McClure, 2019;Stadelmann et al, 2020;Buckton et al, 2021). Extending studies of this nature to macrocyclic hybrids is expected to improve their oral bioavailability for systemic uses.…”

Section: Limitations and Ways Forward In Macrocycle-antibiotic Hybrid Approachmentioning

confidence: 99%

Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

Surur

Sun

2021

Front. Chem.

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The tale of abate in antibiotics continued defense mechanisms that chaperone the rise of drug-defying superbugs—on the other hand, the astray in antibacterial drug discovery and development. Our salvation lies in circumventing the genesis of resistance. Considering the competitive advantages of antibacterial chemotherapeutic agents equipped with multiple warheads against resistance, the development of hybrids has rejuvenated. The adoption of antibiotic hybrid paradigm to macrocycles has advanced novel chemical entities to clinical trials. The multi-targeted TD-1792, for instance, retained potent antibacterial activities against multiple strains that are resistant to its constituent, vancomycin. Moreover, the antibiotic conjugation of rifamycins has provided hybrid clinical candidates with desirable efficacy and safety profiles. In 2020, the U.S. FDA has granted an orphan drug designation to TNP-2092, a conjugate of rifamycin and fluoroquinolone, for the treatment of prosthetic joint infections. DSTA4637S is a pioneer antibacterial agent under clinical development and represents a novel class of bacterial therapy, that is, antibody–antibiotic conjugates. DSTA4637S is effective against the notorious persistent S. aureus bacteremia, a revelation of the abracadabra potential of antibiotic hybrid approaches.

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A Specialized Dehydrogenase Provides l‐Phenyllactate for FR900359 Biosynthesis

et al. 2021

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d-Phenyllactate (PLA) is a component of the selective Gq protein inhibitor and nonribosomal cyclic depsipeptide FR900359 (FR). Here we report a detailed biochemical investigation of PLA biosynthesis and its incorporation into the natural product FR. The enzyme FrsC, member of the lactate/ malate dehydrogenase superfamily, was shown to catalyze the formation of l-PLA from phenylpyruvate. FrsC was kinetically characterized and its substrate specificity determined. Incorporation of l-PLA was probed by assaying the adenylation domain FrsE-A3 and feeding studies with a Chromobacterium vaccinii ΔfrsC mutant, confirming preferred activation of l-PLA followed by on-line epimerization to d-PLA. Finally, detailed bioinformatic analyses of FrsC revealed its close relation to malate dehydrogenases from primary metabolism and suggest extensions in the substrate binding loop to be responsible for its adaptation to accepting larger aromatic substrates with high specificity.

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Connecting the conformational behavior of cyclic octadepsipeptides with their ionophoric property and membrane permeability

Abstract: Cyclic octadepsipeptides such as PF1022A and its synthetic derivative emodepside exhibit anthelmintic activity with the latter sold as a commercial drug treatment against gastrointestinal nematodes for animal health use. The...

Cited by 12 publications

References 83 publications

A Bidirectional Permeability Assay for beyond Rule of 5 Compounds

A Bidirectional Permeability Assay for beyond Rule of 5 Compounds

Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

A Specialized Dehydrogenase Provides l‐Phenyllactate for FR900359 Biosynthesis

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