title: Tiered analytics for purity assessment of macrocyclic peptides in drug discovery: Analytical consideration and method development.
abstract: Synthetic macrocyclic peptides with natural and unnatural amino acids have gained considerable attention from a number of pharmaceutical/biopharmaceutical companies in recent years as a promising approach to drug discovery, particularly for targets involving protein-protein or protein-peptide interactions. Analytical scientists charged with characterizing these leads face multiple challenges including dealing with a class of complex molecules with the potential for multiple isomers and variable charge states and no established standards for acceptable analytical characterization of materials used in drug discovery. In addition, due to the lack of intermediate purification during solid phase peptide synthesis, the final products usually contain a complex profile of impurities. In this paper, practical analytical strategies and methodologies were developed to address these challenges, including a tiered approach to assessing the purity of macrocyclic peptides at different stages of drug discovery. Our results also showed that successful progression and characterization of a new drug discovery modality benefited from active analytical engagement, focusing on fit-for-purpose analyses and leveraging a broad palette of analytical technologies and resources.
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: jingfang.cutrone@bms.com.
authors.forename: Jingfang Jenny
authors.initials: JJ
authors.lastname: Qian Cutrone
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Xiaohua Stella
authors.initials: XS
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kozlowski
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Poronsky
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Dieter M
authors.initials: DM
authors.lastname: Drexler
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, P.O. Box 4000, Princeton, NJ 08543, USA.
authors.forename: Adrienne A
authors.initials: AA
authors.lastname: Tymiak
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D010455:Peptides / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D010455:Peptides
keywords: Chromatography; Drug discovery; Macrocyclic peptide; Purity assessment; Tiered analytics