Strategies for transitioning macrocyclic peptides to cell-permeable drug leads

Walport, Louise J.; Obexer, Richard; Suga, Hiroaki

doi:10.1016/j.copbio.2017.07.007

Cited by 64 publications

(53 citation statements)

References 73 publications

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“…For this purpose, peptides with structural characteristics similar to cyclosporine A will be ideal. [22][23][24] Therefore, the developed analytical method in our system is advantageous for the rapid and efficient analysis of these cyclic peptides, because our system enables satisfactory retention of the peak while realizing a high plate number at a high column temperature. Furthermore, our results suggest that studying the retention behavior of cyclic peptides on our HPLC system can be used for evaluation of the physicochemical characteristics (including primary, secondary, and tertiary structures) of cyclic peptides that contribute to the cellular permeability.…”

Section: Discussionmentioning

confidence: 99%

Rapid Analysis of Cyclic Peptide Cyclosporine A by HPLC Using a Column Packed with Nonporous Particles

Sakai‐Kato¹,

Nanjo²,

Goda³

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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We developed a rapid and efficient analytical technique for cyclosporine A using HPLC on a column packed with 2-µm nonporous octadecylsilyl silica particles. Under optimized conditions, cyclosporine A was separated with high resolution from other cyclic peptides within 3 min, because the mass transfer resistance in the stationary phase was reduced by the use of the small, nonporous particles. Although the plate number increased greatly with the increase in the column temperature, the retention times were not affected. This behavior is different from other cyclic peptides or linear peptides. Based on its physicochemical characteristics, cyclosporine A is a poor hydrogen bond donor, and has a small topological polar surface area, low rotatable bond count, and high log P value. These results show that cyclosporine A is structurally rigid and undergoes poor water solvation even at high temperature. In the context of the rapid development of cyclic peptides with similar physicochemical characteristics to cyclosporine A, our developed method is useful for the development of cyclic peptide therapeutics.

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Section: Discussionmentioning

confidence: 99%

Rapid Analysis of Cyclic Peptide Cyclosporine A by HPLC Using a Column Packed with Nonporous Particles

Sakai‐Kato¹,

Nanjo²,

Goda³

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Such nucleic acid‐encoded libraries can be synthesized and screened in just days to weeks when combined with NGS and have been used to identify lead compounds for an array of high‐priority drug targets, including bacterial transporters, mammalian cell surface receptors, and intercellular proteins and enzymes . It is important to also note that a vast majority of macrocyclic‐peptide inhibitors are unable to penetrate cells, and new advances in drug delivery and/or medicinal chemistry will be necessary to fully realize the potential and versatility of these molecules …”

Section: Hijacking the Ribosome: Co‐translational Nucleic‐acid Barcodmentioning

confidence: 99%

“…[84] It is important to also note that avast majority of macrocyclicpeptide inhibitors are unable to penetrate cells,a nd new advances in drug delivery and/or medicinal chemistry will be necessary to fully realize the potential and versatility of these molecules. [85]…”

Section: Reviewsmentioning

confidence: 99%

Nucleic Acid‐Barcoding Technologies: Converting DNA Sequencing into a Broad‐Spectrum Molecular Counter

Liszczak

Muir

2019

Angew Chem Int Ed

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The emergence of high-throughput DNA sequencing technologies sparked an immediate revolution in the field of genomics that has rippled into many branches of the life and physical sciences. The remarkable sensitivity, specificity, throughput, and multiplexing capacity that are inherent to massively parallel DNA sequencing have since motivated its use as a broad-spectrum molecular counter in small molecule and peptide-based inhibitor discovery, high-throughput biochemistry, protein and cellular detection and diagnostics, and even materials science. A key aspect of extrapolating DNA sequencing to 'non-traditional' applications is the underlying need to append nucleic acid barcodes to entities of interest. In this review, we describe the chemical and biochemical approaches that have enabled facile nucleic acid barcoding of proteinaceous and non-proteinaceous materials, and provide exciting examples of downstream technologies that have been made possible by DNA-encoded molecules. Considering that commercially available high-throughput sequencers were first released less than 15 years ago, we believe related applications will continue to mature for years to come, and close by proposing potential new frontiers to support this assertion.

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“…Combining a high degree of functional complexity with a restricted conformational flexibility make MPs well‐suited to achieve tight binding to notoriously difficult targets, such as biomolecular interfaces . Moreover, peptide macrocyclization is a straightforward means to reduce protease degradation and can facilitate cellular uptake . Lastly, peptides are genetically encodable and lend themselves to massive parallel screening and selection efforts that allow for identifying tight binders from randomized populations.…”

Section: Selection: Ncaas In Peptide Macrocyclizationmentioning

confidence: 99%

Selection, Addiction and Catalysis: Emerging Trends for the Incorporation of Noncanonical Amino Acids into Peptides and Proteins in Vivo

Mayer

2019

ChemBioChem

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Expanding the genetic code of organisms by incorporating noncanonical amino acids (ncAAs) into target proteins through the suppression of stop codons in vivo has profoundly impacted how we perform protein modification or detect proteins and their interaction partners in their native environment. Yet, with genetic code expansion strategies maturing over the past 15 years, new applications that make use—or indeed repurpose—these techniques are beginning to emerge. This Concept article highlights three of these developments: 1) The incorporation of ncAAs for the biosynthesis and selection of bioactive macrocyclic peptides with novel ring architectures, 2) synthetic biocontainment strategies based on the addiction of microorganisms to ncAAs, and 3) enzyme design strategies, in which ncAAs with unique functionalities enable the catalysis of new‐to‐nature reactions. Key advances in all three areas are presented and potential future applications discussed.

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Strategies for transitioning macrocyclic peptides to cell-permeable drug leads

Cited by 64 publications

References 73 publications

Rapid Analysis of Cyclic Peptide Cyclosporine A by HPLC Using a Column Packed with Nonporous Particles

Rapid Analysis of Cyclic Peptide Cyclosporine A by HPLC Using a Column Packed with Nonporous Particles

Nucleic Acid‐Barcoding Technologies: Converting DNA Sequencing into a Broad‐Spectrum Molecular Counter

Selection, Addiction and Catalysis: Emerging Trends for the Incorporation of Noncanonical Amino Acids into Peptides and Proteins in Vivo

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