Biotransformation novel advances – 2021 year in review

Khojasteh, S. Cyrus; Argikar, Upendra A.; Cho, Sungjoon; Crouch, Rachel D.; Heck, Carley J S; Johnson, Kevin M.; Kalgutkar, Amit S.; King, Leslie A.; Maw, Hlaing; Seneviratne, Herana Kamal; Wang, Shuai; Wei, Cong; Zhang, Donglu; Jackson, Klarissa D.

doi:10.1080/03602532.2022.2097253

Cited by 5 publications

(2 citation statements)

References 109 publications

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“…Understanding the underlying mechanisms behind the ADC biotransformation is critical to advance the drug candidate through discovery and development 20 . While for small molecule drug candidates, the ADME studies and metabolite ID analysis is routinely performed, the biotransformation of https://doi.org/10.26434/chemrxiv-2024-04kgm ORCID: https://orcid.org/0000-0003-1939-951X Content not peer-reviewed by ChemRxiv.…”

Section: Discussionmentioning

confidence: 99%

Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying its Stability In Vivo

Huang,

Tan,

Yuan

et al. 2024

Preprint

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What happens to macromolecules in vivo? What drives structure-activity relationship and in vivo stability for antibody-drug conjugates (ADCs)? These interrelated questions are increasingly relevant due to re-emerging importance of ADCs as an impactful therapeutic modality and the gaps that exist in our understanding of ADC structural determinants that underlie ADC in vivo stability. Complex macromolecules, such as ADCs, may undergo changes in vivo due to their intricate structure as biotransformations may occur on the linker, the payload and/or at the modified conjugation site. Dissection of ADC metabolism presents a substantial analytical challenge due to the difficulty in identification or quantification of minor changes on a large macromolecule. We employed immunocapture-LCMS methods to evaluate in vivo changes in DAR profile in four different lead ADCs. This resulted in selection of AZD8205, a B7-H4-directed cysteine-conjugated ADC bearing a topoisomerase I inhibitor payload, with durable DAR. The results showed that vast majority of the biotransformation species identified contained at least one payload. This comprehensive characterization revealed that critical structural determinant contributing to the design of AZD8205 was the PEG section of the linker, resulting in competition between linker deconjugation and maleimide hydrolysis reactions resulting in a durable high DAR in vivo. To our knowledge, this study is the most extensive characterization of ADC in vivo biotransformation to date, which also sheds light on determinants of ADC stability in vivo and informs the selection of optimal linker. These results highlight the relevance of studying macromolecule biotransformation in elucidating the ADC structure-in vivo stability relationship.

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Section: Discussionmentioning

confidence: 99%

Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying its Stability In Vivo

Huang,

Tan,

Yuan

et al. 2024

Preprint

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“…Many factors affect microbial transformation, such as fermentation mode, culture medium type, fermentation temperature, humidity, time, pH, rotation speed, substrate solubility, and co-factors [ 7 , 9 , 10 , 11 , 12 , 13 , 14 ]. Moreover, due to the existence of plant enzyme systems and the differences of oxygen content, the products of solid-state fermentation and liquid fermentation are quite different [ 9 , 15 , 16 , 17 ]. For example, microorganisms secrete different enzymes at different times in the biotransformation process, which makes the characteristic metabolites have characteristic generation times.…”

Section: Introductionmentioning

confidence: 99%

Multi-Level Optimization and Strategies in Microbial Biotransformation of Nature Products

Qin

Dong

2023

Molecules

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Continuously growing demand for natural products with pharmacological activities has promoted the development of microbial transformation techniques, thereby facilitating the efficient production of natural products and the mining of new active compounds. Furthermore, due to the shortcomings and defects of microbial transformation, it is an important scientific issue of social and economic value to improve and optimize microbial transformation technology in increasing the yield and activity of transformed products. In this review, the aspects regarding the optimization of fermentation and the cross-disciplinary strategy, leading to the microbial transformation of increased levels of the high-efficiency process from natural products of a plant or microbial origin, were discussed. Additionally, due to the increasing craving for targeted and efficient methods for detecting transformed metabolites, analytical methods based on multiomics were also discussed. Such strategies can be well exploited and applied to the production of more efficient and more natural products from microbial resources.

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Microbial Biotransformation of 1-Methyl-L-tryptophan into Herbicidal Indole Alkaloids by Endophytic Fungus Nigrospora chinensis GGY-3

Wang,

He,

Zuo

et al. 2024

J. Org. Chem.

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Indole alkaloids are privileged secondary metabolites, and their production may be achieved by the microbial biotransformation of tryptophan analogues. By feeding 1-methyl-Ltryptophan (1-MT) into the culture of endophytic Nigrospora chinensis GGY-3, six novel (1−6) and seven known indole alkaloids (7−13) were generated. Their structures were elucidated by means of NMR spectroscopy, experimental electronic circular dichroism (ECD) spectra, and X-ray crystallography analysis. A Friedel− Crafts reaction was proposed as the key reaction responsible for the formation of the new compounds. Racemates 4 and 6 were separated into isomers by chiral HPLC, with their absolute configurations determined by X-ray and ECD calculation. Compounds 3, 4, and 8 display good herbicidal activity against dicotyledon weed Eclipta prostrata, of which 4 and 8 exhibited 88.50% and 100% inhibition rates on the radicle at 200 μg/mL, respectively, a similar effect compared to the positive control penoxsulam.

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Biotransformation novel advances – 2021 year in review

Cited by 5 publications

References 109 publications

Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying its Stability In Vivo

Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying its Stability In Vivo

Multi-Level Optimization and Strategies in Microbial Biotransformation of Nature Products

Microbial Biotransformation of 1-Methyl-L-tryptophan into Herbicidal Indole Alkaloids by Endophytic Fungus Nigrospora chinensis GGY-3

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