Accurate de novo design of membrane-traversing macrocycles

Bhardwaj, Gaurav; O’Connor, Jacob; Rettie, Stephen A.; Huang, Yen‐Hua; Ramelot, Theresa; Mulligan, Vikram Khipple; Alpkilic, Gizem Gokce; Palmer, Jonathan M.; Bera, Asim K.; Bick, Matthew J.; Piazza, Maddalena Di; Li, Xinting; Hosseinzadeh, Parisa; Craven, Timothy W.; Tejero, Roberto; Lauko, Anna; Choi, Ryan; Glynn, Calina; Dong, Li Min; Griffin, Robert; Voorhis, Wesley C. Van; Rodriguez, Jose J. Sanchez; Stewart, Lance; Montelione, Gaetano T.; Craik, David J.; Baker, David

doi:10.1016/j.cell.2022.07.019

Cited by 83 publications

(74 citation statements)

References 74 publications

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“…With current Nanoscale Horizons technology, it may be difficult to experimentally construct a pump system with the mechanism we propose. On the other hand, de novo protein designs have been actively proposed recently [60][61][62] .…”

Section: Discussionmentioning

confidence: 99%

Wetting hysteresis induces effective unidirectional water transport through a fluctuating nanochannel

et al. 2023

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Section: Discussionmentioning

confidence: 99%

Wetting hysteresis induces effective unidirectional water transport through a fluctuating nanochannel

et al. 2023

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“…While the current generation of macrocycles are not active within cells, enhancing the permeability of such compounds is a topic of intense current interest. Accordingly, we anticipate that application of emerging strategies, including promising new experimental [50,51] and computational methods, [52] to these series of macrocyclic OGT inhibitors will be a productive future line of research that will ultimately deliver selective cell-active allosteric OGT inhibitors. Finally, the ability to append a biotin affinity tag to these OGT-targeted macro-cycles, without perturbing the high affinity of these compounds, enables the efficient isolation of OGT samples through a simple one-step affinity purification.…”

Section: Discussionmentioning

confidence: 99%

Potent De Novo Macrocyclic Peptides That Inhibit O‐GlcNAc Transferase through an Allosteric Mechanism

et al. 2022

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Glycosyltransferases are a superfamily of enzymes that are notoriously difficult to inhibit. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non-standard peptides integrated discovery) system, to identify macrocyclic peptides with high binding affinities for O-GlcNAc transferase (OGT). These macrocycles inhibit OGT activity through an allosteric mechanism that is driven by their binding to the tetratricopeptide repeats of OGT. Saturation mutagenesis in a maturation screen using 39 amino acids, including 22 non-canonical residues, led to an improved unnatural macrocycle that is � 40 times more potent than the parent compound (K i app = 1.5 nM). Subsequent derivatization delivered a biotinylated derivative that enabled one-step affinity purification of OGT from complex samples. The high potency and novel mechanism of action of these OGT ligands should enable new approaches to elucidate the specificity and regulation of OGT.

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“…Introduction of tertiary amides in macrocycles thus appears to be a particularly powerful strategy for the design of molecular chameleons, as demonstrated recently in a systematic approach to the de novo design of chameleonic cyclic peptides. [85] Qualitative correlations to cell permeability Drugs are generally assumed to be absorbed from the intestine and to enter target cells by passive permeability across cell membranes. [86] Different mechanistic models have been proposed for how passive cell permeability of compounds in the bRo5 space may occur.…”

Section: Subclassification Of Molecular Chameleonsmentioning

confidence: 99%

Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds

Wieske

Atilaw

Poongavanam

et al. 2022

Chemistry A European J

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The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d 6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d 6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.

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Accurate de novo design of membrane-traversing macrocycles

Cited by 83 publications

References 74 publications

Wetting hysteresis induces effective unidirectional water transport through a fluctuating nanochannel

Wetting hysteresis induces effective unidirectional water transport through a fluctuating nanochannel

Potent De Novo Macrocyclic Peptides That Inhibit O‐GlcNAc Transferase through an Allosteric Mechanism

Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds

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