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Macrocycle synthesis strategy based on step-wise "adding and reacting" three components enables screening of large combinatorial libraries.

ABSTRACT: Macrocycles provide an attractive modality for drug development, but generating ligands for new targets is hampered by the limited availability of large macrocycle libraries. We have established a solution-phase macrocycle synthesis strategy in which three building blocks are coupled sequentially in efficient alkylation reactions that eliminate the need for product purification. We demonstrate the power of the approach by combinatorially reacting 15 bromoacetamide-activated tripeptides, 42 amines, and 6 bis-electrophile cyclization linkers to generate a 3780-compound library with minimal effort. Screening against thrombin yielded a potent and selective inhibitor (K _i = 4.2 ± 0.8 nM) that efficiently blocked blood coagulation in human plasma. Structure-activity relationship and X-ray crystallography analysis revealed that two of the three building blocks acted synergistically and underscored the importance of combinatorial screening in macrocycle development. The three-component library synthesis approach is general and offers a promising avenue to generate macrocycle ligands to other targets.

SUBMITTER: Mothukuri GK

PROVIDER: S-EPMC8163216 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Macrocycle synthesis strategy based on step-wise "adding and reacting" three components enables screening of large combinatorial libraries.

Mothukuri Ganesh K GK Kale Sangram S SS Stenbratt Carl L CL Zorzi Alessandro A Vesin Jonathan J Bortoli Chapalay Julien J Deyle Kaycie K Turcatti Gerardo G Cendron Laura L Angelini Alessandro A Heinis Christian C

Chemical science 20200626 30

Macrocycles provide an attractive modality for drug development, but generating ligands for new targets is hampered by the limited availability of large macrocycle libraries. We have established a solution-phase macrocycle synthesis strategy in which three building blocks are coupled sequentially in efficient alkylation reactions that eliminate the need for product purification. We demonstrate the power of the approach by combinatorially reacting 15 bromoacetamide-activated tripeptides, 42 amine ...[more]

PMID: 34094158

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Project description:BackgroundAn epidural steroid injection (ESI) is used to treat a number of morbid central nervous system pathologies and is considered a reasonably safe procedure. This study aimed to determine the relative infection risk after spinal surgery by comparing outcomes in spinal surgery patients who received an ESI shortly prior to the surgery against those who did not receive an ESI shortly prior to the surgery.MethodsThe present study is a retrospective cohort study using a multi-institutional healthcare database, TriNetX, to collect data on patients who received spinal surgery with and without having had ESIs six months before surgery. Two cohorts were generated: Cohort 1 included patients who had received an ESI in the six months prior to spinal surgery, and cohort 2 included patients who did not have an ESI in the six months prior to spinal surgery. The patients in cohort 2 had propensity scores matched 1:1 to those in cohort 1 using common baseline demographics, comorbidities and spinal procedure indications. The spinal procedures and surgeries considered for the analysis included open procedures for any purpose, including exploration, decompression, resection, revision or biopsy. Multiple outcomes were compared across these two cohorts in the three months following the spinal procedure/surgery, including the occurrence of death, surgical site infection, epidural and/or spinal abscess, and dural tear.ResultsAn ESI in the six months prior to spinal surgery was associated with a significant decrease in the likelihood epidural/spinal abscess in the three months after surgery. There was no change in mortality, wound infection or identification of dural tear in the three months after spinal surgery for those who received an ESI six months before spinal surgery.ConclusionThis data suggests that epidural steroid injections' anti-inflammatory effects provide benefits before surgery beyond symptomatic relief. Given that the degeneration of spinal pathologies is typically advanced rather than corrected by the body's inflammatory response, it is likely that preventing hyperactivation of the body's immune system in the months preceding surgical intervention, a traumatic insult, is protective compared to no intervention and, importantly, without major adverse effects.

Dataset Information

Macrocycle synthesis strategy based on step-wise "adding and reacting" three components enables screening of large combinatorial libraries.

Publications

Macrocycle synthesis strategy based on step-wise "adding and reacting" three components enables screening of large combinatorial libraries.

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