Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties

Zambaldo, Claudio; Daguer, Jean‐Pierre; Saarbach, Jacques; Barluenga, Sofía; Winssinger, Nicolas

doi:10.1039/c6md00242k

Cited by 60 publications

(41 citation statements)

References 67 publications

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“…[45] The emergence of DNA-encoding as a rapid method to screen libraries of small molecules [46] is poised to make an impact in this area and novel screening methods to differentiate covalent from high affinity non-covalent inhibitor in a primary affinity screen have been reported. [47] In parallel, the development of novel reagents that broadly label cysteines will further enhance our ability to assess target selectivity without recourse to an inhibitor conjugated to a tag. [48] This is important because such conjugation can bias target engagement or be synthetically demanding…”

Section: Resultsmentioning

confidence: 99%

Covalent inhibitors: an opportunity for rational target selectivity

Lagoutte

Patouret

Winssinger

2017

Current Opinion in Chemical Biology

114

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There is a resurging interest in compounds that engage their target through covalent interactions. Cysteine's thiol is endowed with enhanced reactivity, making it the nucleophile of choice for covalent engagement with a ligand aligning an electrophilic trap with a cysteine residue in a target of interest. The paucity of cysteine in the proteome coupled to the fact that closely related proteins do not necessarily share a given cysteine residue enable a level of unprecedented rational target selectivity. The recent demonstration that a lysine's amine can also be engaged covalently with a mild electrophile extends the potential of covalent inhibitors. The growing database of protein structures facilitates the discovery of covalent inhibitors while the advent of proteomic technologies enables a finer resolution in the selectivity of covalently engaged proteins. Here, we discuss recent examples of discovery and design of covalent inhibitors.

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Section: Resultsmentioning

confidence: 99%

Covalent inhibitors: an opportunity for rational target selectivity

Lagoutte

Patouret

Winssinger

2017

Current Opinion in Chemical Biology

114

View full text Add to dashboard Cite

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“…[25] Large compound collections,d isplayed at the extremities of complementary DNAstrands that can combinatorially self-assemble, can be screened using dual-pharmacophore encoded chemical library technology. [27] Similar procedures could be implemented for the discovery of reversible covalent binders by incorporating 2-hydroxybenzaldehyde or similar moieties during library construction. [27] Similar procedures could be implemented for the discovery of reversible covalent binders by incorporating 2-hydroxybenzaldehyde or similar moieties during library construction.…”

Section: Angewandte Chemiementioning

confidence: 99%

Affinity Enhancement of Protein Ligands by Reversible Covalent Modification of Neighboring Lysine Residues

et al. 2018

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The discovery of protein ligands,capable of forming ar eversible covalent bond with amino acid residues on ap rotein target of interest, may represent ag eneral strategy for the discovery of potent small-molecule inhibitors.W e analyzed the ability of different aromatic aldehydes to form imines by reaction with lysine using 1 HNMR techniques.2 -Hydroxybenzaldehyde derivatives were found to efficiently form imines in the millimolar concentration range.T hese benzaldehyde derivatives could increase the binding affinity of protein ligands towards the cognate protein target. Affinity maturation was achieved not only by displaying ligand and aldehyde moieties on two complementary locked nucleic acid strands but also by incorporating the binding fragments in as ingle small-molecule ligand. The affinity gain was only observed when lysine residues were accessible in the immediate surroundings of the ligand-binding site and could be abrogated by quenching with amolar excess of hydroxylamine. Conflict of interestD.N. is ac o-founder and shareholder of Philogen (www.philogen.com), aSwiss-Italian Biotech company that operates in the field of DNA-Encoded Chemical Libraries.J .S.isaboard member of Philochem AG (www.philochem.ch).

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“…Large compound collections, displayed at the extremities of complementary DNA strands that can combinatorially self‐assemble, can be screened using dual‐pharmacophore encoded chemical library technology . DNA‐encoded libraries have previously been used to discover irreversible covalent inhibitors . Similar procedures could be implemented for the discovery of reversible covalent binders by incorporating 2‐hydroxybenzaldehyde or similar moieties during library construction.…”

Section: Figurementioning

confidence: 99%

Affinity Enhancement of Protein Ligands by Reversible Covalent Modification of Neighboring Lysine Residues

et al. 2018

View full text Add to dashboard Cite

The discovery of protein ligands, capable of forming a reversible covalent bond with amino acid residues on a protein target of interest, may represent a general strategy for the discovery of potent small‐molecule inhibitors. We analyzed the ability of different aromatic aldehydes to form imines by reaction with lysine using 1H NMR techniques. 2‐Hydroxybenzaldehyde derivatives were found to efficiently form imines in the millimolar concentration range. These benzaldehyde derivatives could increase the binding affinity of protein ligands towards the cognate protein target. Affinity maturation was achieved not only by displaying ligand and aldehyde moieties on two complementary locked nucleic acid strands but also by incorporating the binding fragments in a single small‐molecule ligand. The affinity gain was only observed when lysine residues were accessible in the immediate surroundings of the ligand‐binding site and could be abrogated by quenching with a molar excess of hydroxylamine.

show abstract

Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties

Cited by 60 publications

References 67 publications

Covalent inhibitors: an opportunity for rational target selectivity

Covalent inhibitors: an opportunity for rational target selectivity

Affinity Enhancement of Protein Ligands by Reversible Covalent Modification of Neighboring Lysine Residues

Affinity Enhancement of Protein Ligands by Reversible Covalent Modification of Neighboring Lysine Residues

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