Expanding the Chemical Diversity of Genetically Encoded Libraries

Iskandar, Sabrina E; Haberman, Victoria A; Bowers, A.

doi:10.1021/acscombsci.0c00179

Cited by 31 publications

(28 citation statements)

References 231 publications

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“…The N ‐terminus is unique in its reactivity and can hence be utilized as a handle for a number of chemical post‐translational modifications on top of the amine modifications used with lysine, [84] although it is not always accessible for chemical modification (for example remaining formylated in some bacterial‐derived in vitro translation systems). One such unique functionality of the N ‐terminus is the mild nucleophilicity of the downstream amide bond to trap transient adducts.…”

Section: Chemistry Compatible With Nucleic Acid Tagsmentioning

confidence: 99%

Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA‐Displayed Peptide Libraries

2022

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DNA‐encoded small‐molecule libraries and mRNA displayed peptide libraries both use numerically large pools of oligonucleotide‐tagged molecules to identify potential hits for protein targets. They differ dramatically, however, in the ‘drug‐likeness’ of the molecules that each can be used to discover. We give here an overview of the two techniques, comparing some advantages and disadvantages of each, and suggest areas where particularly mRNA display can benefit from adopting advances developed with DNA‐encoded small molecule libraries. We outline cases where chemical modification of the peptide library has already been used in mRNA display, and survey opportunities to expand this using examples from DNA‐encoded small molecule libraries. We also propose potential opportunities for encoding such reactions within the mRNA/cDNA tag of an mRNA‐displayed peptide library to allow a more diversity‐oriented approach to library modification. Finally, we outline alternate approaches for enriching target‐binding hits from a pooled and tagged library, and close by detailing several examples of how an adjusted mRNA‐display based approach could be used to discover new ‘drug‐like’ modified small peptides.

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Section: Chemistry Compatible With Nucleic Acid Tagsmentioning

confidence: 99%

Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA‐Displayed Peptide Libraries

2022

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“…Receptor-targeted phage display peptides, for example, bind at or near insulin's native receptor-binding sites but stimulate a distinct pattern of signaling outputs [ [228] , [229] , [230] ]. Yeast display technology may enable this approach to generalize to libraries of insulin variants [ [231] , [232] , [233] ] as demonstrated by Chou and colleagues [ 234 ]. The concept of biased agonism may also be exploited to reduce the baseline mitogenicity of insulin, of interest in relation to epidemiological relationships between T2D and several common cancers [ [235] , [236] , [237] ].…”

Section: Next-generation Insulin Analogsmentioning

confidence: 99%

Structural principles of insulin formulation and analog design: A century of innovation

Jarosinski

Dhayalan

Chen

et al. 2021

Molecular Metabolism

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Background The discovery of insulin in 1921 and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front, from the stabilization of animal insulin formulations to the frontiers of synthetic peptide chemistry, and in turn, from the advent of recombinant DNA manufacturing to structure-based protein analog design. In each case, a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding. Scope of review Pioneering crystallographic analyses—beginning with Hodgkin's solving of the 2-Zn insulin hexamer—elucidated general features of protein self-assembly, including zinc coordination and the allosteric transmission of conformational change. Crystallization of insulin was exploited both as a step in manufacturing and as a means of obtaining protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs. Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic (PK) properties. Encouraged by clinical trials demonstrating the long-term importance of glycemic control, regimens based on such analogs sought to resemble daily patterns of endogenous β-cell secretion more closely, ideally with reduced risk of hypoglycemia. Major conclusions Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics.

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“…23 To mitigate this issue, we sought to replace the disulfide bond with a nonreducible linkage prior to the screen. [28][29][30] First, we performed post-translational modification of all three phage libraries with either 1,3-dibromoacetone (Fig. 1b) or α,α′dibromo-p-xylene (Fig.…”

Section: Hit Identification With Phage Displaymentioning

confidence: 99%

Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1

Ng¹,

Brueckner

Bahmanjah

et al. 2021

Preprint

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STIP1 homology and U-Box containing protein 1 (STUB1) plays a key role in maintaining cell health during stress and aging. Recent evidence suggested STUB1 also helps regulate immunity with the potential of clearing malignant cells. Indeed, we and others have shown that STUB1 is a pivotal negative regulator of interferon gamma sensing – a process critical to the immunosurveillance of tumors and pathogens. Thus far, investigation of STUB1’s role relies mostly on genetic approaches as pharmacological inhibitors of this protein are lacking. Identification of a STUB1 tool compound is important as it would allow therapeutically relevant target validation in a broader sense. Accordingly, we leveraged phage display and computational modeling to identify and refine STUB1 binders. Screening of >10E9 macrocyclic peptides resulted in several conserved motifs as well as structurally diverse leads. Co-crystal structure of the peptide hit and STUB1 has enabled us to employ structure-based in silico design for further optimization. Of the modifications employed, replacing the hydrophilic solvent-exposed region of the macrocyclic peptides with a hydrophobic scaffold improved cellular permeability, while the binding conformation was maintained. Further substitution of the permeability-limiting terminal aspartic acid with a tetrazole bioisostere retained the binding to certain extent while improving permeability, suggesting a path forward. The current lead, although not optimal for cellular study, provides a valuable template for further development into selective tool compounds for STUB1 to enable target validation.

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Expanding the Chemical Diversity of Genetically Encoded Libraries

Cited by 31 publications

References 231 publications

Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA‐Displayed Peptide Libraries

Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA‐Displayed Peptide Libraries

Structural principles of insulin formulation and analog design: A century of innovation

Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1

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