Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps DOI
Lin Yang, Kaiyue Zhang,

Meng Xu

et al.

Angewandte Chemie, Journal Year: 2022, Volume and Issue: 134(52)

Published: Oct. 27, 2022

Abstract ω‐Transaminases (ω‐TAs) show considerable potential for the synthesis of chiral amines. However, their low catalytic efficiency towards bulky substrates limits application, and complicated mechanisms prevent precise enzyme design. Herein, we address this challenge using a mechanism‐guided computational design strategy by reprograming transition ground states in key reaction steps. The common features among three high‐energy‐barrier steps responsible were revealed quantum mechanics (QM). Five residues simultaneously tailored to stabilize rate‐limiting state with aid Rosetta 14 top‐ranked variants showed 16.9–143‐fold improved activity. best variant, M9 (Q25F/M60W/W64F/I266A), was significantly increased, 1660‐fold increase k cat / K m 1.5–26.8‐fold turnover number (TON) various indanone derivatives.

Language: Английский

Review article: Risk of cardiovascular events in patients with inflammatory bowel disease receiving small molecule drugs DOI Creative Commons
Pablo A. Olivera, Juan S. Lasa, Giovanni Peretto

et al.

Alimentary Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 57(11), P. 1231 - 1248

Published: April 10, 2023

Summary Background In the context of an ageing inflammatory bowel disease (IBD) population, cardiovascular comorbidities become particularly relevant. Novel small molecule drugs (SMDs) for treatment moderate‐to‐severe IBD have been recently approved, including Janus kinase (JAK) inhibitors and sphingosine‐1‐phosphate receptor (S1P) modulators. Data from rheumatoid arthritis population raised concerns about risk events with use tofacitinib, which was extrapolated to other immune‐mediated diseases JAK inhibitors. S1P modulation has associated potential events, especially bradycardia cardiac conduction abnormalities. Aim To review incidence SMDs in patients provide practical recommendations on mitigation strategies. Methods Published literature reviewed; were synthesised by experts both IBD. Results Evidence does not indicate a higher tofacitinib The is intermediate high risk. modulators may be dose‐dependent, first‐dose effect, transient abnormalities (bradycardia AV block). Screening monitoring factors should done all Risk stratification performed before starting SMDs. Conclusions Available evidence indicates reassuring safety profile perspective overall population. Efforts made identify at events.

Language: Английский

Citations

20
Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps DOI
Lin Yang, Kaiyue Zhang, Meng Xu

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(52)

Published: Oct. 27, 2022

Abstract ω‐Transaminases (ω‐TAs) show considerable potential for the synthesis of chiral amines. However, their low catalytic efficiency towards bulky substrates limits application, and complicated mechanisms prevent precise enzyme design. Herein, we address this challenge using a mechanism‐guided computational design strategy by reprograming transition ground states in key reaction steps. The common features among three high‐energy‐barrier steps responsible were revealed quantum mechanics (QM). Five residues simultaneously tailored to stabilize rate‐limiting state with aid Rosetta 14 top‐ranked variants showed 16.9–143‐fold improved activity. best variant, M9 (Q25F/M60W/W64F/I266A), was significantly increased, 1660‐fold increase k cat / K m 1.5–26.8‐fold turnover number (TON) various indanone derivatives.

Language: Английский

Citations

23
The Role of Patient-Reported Outcomes to Measure Treatment Satisfaction in Drug Development DOI Creative Commons
Carolina Navas,

Alexandra Palmer Minton,

Ana Maria Rodriguez-Leboeuf

et al.

Patient, Journal Year: 2024, Volume and Issue: 17(6), P. 603 - 617

Published: July 8, 2024

Treatment satisfaction is a person's rating of his or her treatment experience, including processes and outcomes. It directly related to adherence, which may be predictive effectiveness in clinical real-world research. Consequently, patient-reported outcome (PRO) instruments have been developed incorporate patient experience throughout various stages drug development routine care. PRO enable clinicians researchers evaluate compare data different settings. important select fit-for-purpose that demonstrated adequate levels reliability, validity, sensitivity change support their use. Some these are unidimensional while some multidimensional; generic can applied across therapeutic areas, others for use specific modality condition. This article describes the role as well regulatory Health Technology Assessment (HTA) decision making calls more widespread carefully selected early- late-phase development.

Language: Английский

Citations

2
Impact of Disease Modifying Therapy on MS-Related Fatigue: A Narrative Review DOI Creative Commons
Mahmoud Elkhooly,

Fen Bao,

Evanthia Bernitsas

et al.

Brain Sciences, Journal Year: 2023, Volume and Issue: 14(1), P. 4 - 4

Published: Dec. 20, 2023

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system by causing inflammation, demyelination and neurodegeneration. Fatigue most prevalent one of disabling symptoms among people with MS (pwMS). Due to its complexity subjective character, fatigue still little understood despite frequent occurrence severe impact. The potential causes, effects, treatments associated have been extensively studied in recent years. Though benefits such variety contributions are obvious, there not many attempts evaluate effect modifying therapies (DMTs) on MS-related fatigue. In this review, we summarize clinical trials research studies, discuss different DMTs

Language: Английский

Citations

3
Mechanism‐Guided Computational Design of ω‐Transaminase by Reprograming of High‐Energy‐Barrier Steps DOI
Lin Yang, Kaiyue Zhang,

Meng Xu

et al.

Angewandte Chemie, Journal Year: 2022, Volume and Issue: 134(52)

Published: Oct. 27, 2022

Abstract ω‐Transaminases (ω‐TAs) show considerable potential for the synthesis of chiral amines. However, their low catalytic efficiency towards bulky substrates limits application, and complicated mechanisms prevent precise enzyme design. Herein, we address this challenge using a mechanism‐guided computational design strategy by reprograming transition ground states in key reaction steps. The common features among three high‐energy‐barrier steps responsible were revealed quantum mechanics (QM). Five residues simultaneously tailored to stabilize rate‐limiting state with aid Rosetta 14 top‐ranked variants showed 16.9–143‐fold improved activity. best variant, M9 (Q25F/M60W/W64F/I266A), was significantly increased, 1660‐fold increase k cat / K m 1.5–26.8‐fold turnover number (TON) various indanone derivatives.

Language: Английский

Citations

1