Engineering a Cytidine Aminotransferase for Biocatalytic Production of the Antiviral Molnupiravir

The COVID-19 pandemic highlights the urgent need for cost-effective processes to rapidly manufacture antiviral drugs at scale. Here we report a concise biocatalytic process for Molnupiravir, a nucleoside analogue currently in phase 3 clinical trials as an orally available treatment for SARS-CoV-2. Key to the success of this process was the development of a cytidine aminotransferase for the production of N-hydroxy-cytidine through evolutionary adaption of the hydrolytic enzyme cytidine deaminase. This engineered biocatalyst performs >100,000 turnovers in less than 30 minutes, operates at 180 g/L substrate loading and benefits from in situ crystallization of the N-hydroxy-cytidine product (>90% yield), which can be converted to Molnupiravir by a selective 5’-acylation using Novozym® 435.

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Efficacy of Certolizumab Pegol for Psoriasis of the Head and Neck in Two Phase 3 Clinical Trials: CIMPASI-1 and CIMPASI-2

SKIN The Journal of Cutaneous Medicine ◽

10.25251/skin.3.supp.40 ◽

2019 ◽

Vol 3 ◽

pp. S40

Author(s):

P Van de Kerkhof ◽

A Pinter ◽

M Boehnlein ◽

S Kavanagh ◽

J.J. Crowley

Keyword(s):

Clinical Trials ◽

Head And Neck ◽

Certolizumab Pegol ◽

Phase 3 ◽

Two Phase

Abstract not available.

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Crisaborole Ointment Provides Early Relief of Pruritus in Two Phase 3 Clinical Trials in Patients With Mild or Moderate Atopic Dermatitis

10.26226/morressier.595a9c52d462b80296c9f5e3 ◽

2017 ◽

Author(s):

Emma Guttman-Yassky

Keyword(s):

Clinical Trials ◽

Atopic Dermatitis ◽

Phase 3 ◽

Two Phase

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Faculty Opinions recommendation of Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717964455.793467666 ◽

2012 ◽

Author(s):

Peter Paine

Keyword(s):

Clinical Trials ◽

Randomised Clinical Trials ◽

European Medicines Agency ◽

Phase 3

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Faculty Opinions recommendation of Efficacy and safety of topical clascoterone cream, 1%, for treatment in patients with facial acne: two phase 3 randomized clinical trials.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737803133.793575042 ◽

2020 ◽

Author(s):

Joel Gelfand ◽

John Barbieri

Keyword(s):

Clinical Trials ◽

Randomized Clinical Trials ◽

Efficacy And Safety ◽

Phase 3 ◽

Two Phase ◽

Facial Acne

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Phase 3 Clinical Trials: D-Methionine to Reduce Noise-Induced Hearing Loss

10.21236/ada579127 ◽

2013 ◽

Author(s):

Kathleen C. Campbell

Keyword(s):

Clinical Trials ◽

Hearing Loss ◽

Noise Induced Hearing Loss ◽

Phase 3

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Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-9.4.214 ◽

2010 ◽

Vol 9 (4) ◽

pp. 214-219

Author(s):

Robyn J. Barst

Keyword(s):

Clinical Trials ◽

Pulmonary Arterial Hypertension ◽

Drug Development ◽

Phase 1 ◽

Preclinical Studies ◽

Phase 2 ◽

Phase 3 ◽

Preclinical Testing ◽

New Drug ◽

Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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New Anti-VEGF Drugs in Ophthalmology

Current Drug Targets ◽

10.2174/1389450121666200428101738 ◽

2020 ◽

Vol 21 (12) ◽

pp. 1194-1200

Author(s):

Claudio Campa

Keyword(s):

Clinical Trials ◽

Delivery System ◽

Clinical Development ◽

Advanced Stage ◽

Phase 3 ◽

Anti Vegf

: This review focuses on 5 new anti-VEGF drugs in the advanced stage of clinical development (i.e., phase 3): conbercept, brolucizumab, port delivery system with ranibizumab, abicipar pegol and faricimab. : Results of clinical trials and the advantages of each drug compared to the available molecules are discussed in detail.

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Fabrication of a liquid cell for in situ transmission electron microscopy

Microscopy ◽

10.1093/jmicro/dfaa076 ◽

2020 ◽

Author(s):

Xiaoguang Li ◽

Kazutaka Mitsuishi ◽

Masaki Takeguchi

Keyword(s):

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Cost Effective ◽

Production Method ◽

Microscopy Imaging ◽

Transmission Electron ◽

In Situ Electron Microscopy ◽

Liquid Cell ◽

Si Wafer

Abstract Liquid cell transmission electron microscopy (LCTEM) enables imaging of dynamic processes in liquid with high spatial and temporal resolution. The widely used liquid cell (LC) consists of two stacking microchips with a thin wet sample sandwiched between them. The vertically overlapped electron-transparent membrane windows on the microchips provide passage for the electron beam. However, microchips with imprecise dimensions usually cause poor alignment of the windows and difficulty in acquiring high-quality images. In this study, we developed a new and efficient microchip fabrication process for LCTEM with a large viewing area (180 µm × 40 µm) and evaluated the resultant LC. The new positioning reference marks on the surface of the Si wafer dramatically improve the precision of dicing the wafer, making it possible to accurately align the windows on two stacking microchips. The precise alignment led to a liquid thickness of 125.6 nm close to the edge of the viewing area. The performance of our LC was demonstrated by in situ transmission electron microscopy imaging of the dynamic motions of 2-nm Pt particles. This versatile and cost-effective microchip production method can be used to fabricate other types of microchips for in situ electron microscopy.

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