A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase

Abstract A worldwide effort is ongoing to discover drugs against the Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2), which has so far caused >3.5 million fatalities (https://covid19.who.int/). The virus essential RNA-dependent RNA polymerase complex is targeted by several nucleoside/tide analogues whose mechanisms of action and clinical potential are currently evaluated. The guanosine analogue AT-527, a double prodrug of its 5'-triphosphate AT-9010, is currently in phase III clinical trials as a COVID19 treatment. Here we report the cryo-EM structure at 2.98 Å resolution of the SARS-CoV-2 nsp12-nsp7-(nsp8)2 complex with RNA showing AT-9010 bound at three sites of nsp12. At the RdRp active-site, one AT-9010 is incorporated into the RNA product. Its 2'-methyl group prevents correct alignment of a second AT-9010 occupying the incoming NTP pocket. The 2'-F, 2'-methyl 3'-OH ribose scaffold explains the non-obligate RNA chain-termination potency of this NA series for both HCV NS5 and SARS-CoV RTCs. A third AT-9010 molecule 5'-diphosphate binds to a coronavirus-specific pocket in the nsp12 N-terminus NiRAN domain, a SelO pseudo-kinase structural and functional homologue. This unique binding mode impedes NiRAN-mediated UMPylation of SARS-CoV-2 nsp8 and nsp9 proteins. Our results suggest a mechanism of action for AT-527 in line with a therapeutic use for COVID19.

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P4-428: Mechanism of action of new Alzheimer's therapeutic in phase III clinical trials

Alzheimer s & Dementia ◽

10.1016/j.jalz.2011.09.124 ◽

2011 ◽

Vol 7 ◽

pp. e61-e61 ◽

Cited By ~ 2

Author(s):

Michael Mullan ◽

Corbin Bachmeier ◽

Ghania Ait-Ghezala ◽

David Beaulieu-Abdelahad ◽

Fiona Crawford ◽

...

Keyword(s):

Clinical Trials ◽

Mechanism Of Action ◽

Phase Iii ◽

Phase Iii Clinical Trials

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Glucose Control and Cardiovascular Outcomes in Clinical Trials of Sodium Glucose Co-transporter 2 Inhibitor Treatments in Type 2 Diabetes

US Endocrinology ◽

10.17925/use.2014.10.01.8 ◽

2014 ◽

Vol 10 (01) ◽

pp. 8

Author(s):

Rene A Oliveros ◽

Son V Pham ◽

Steven R Bailey ◽

Robert J Chilton ◽

◽

...

Keyword(s):

Type 2 Diabetes ◽

Clinical Trials ◽

Glycemic Control ◽

Safety Data ◽

Sglt2 Inhibitors ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

Urinary Glucose ◽

Reduce Blood Glucose

Currently available medications for the treatment of type 2 diabetes have limitations, and many patients do not achieve glycemic control. Recently, a new approach has emerged using sodium glucose co-transporter 2 (SGLT2) inhibitors that decrease glucose reabsorption in the kidneys, increasing urinary glucose excretion. These agents offer the potential to improve glycemic control independently of insulin pathways while avoiding hypoglycemia. Two drugs of this class, canagliflozin and dapagliflozin, have been approved by the US Food and Drug Administration (FDA); another, empagliflozin, has been filed for regulatory approval and several others are in advanced development. These drugs have been shown to effectively reduce blood glucose, fasting plasma glucose, and glycated hemoglobin (HbA1C) levels in phase III clinical trials when used as monotherapy and as add-on therapy to other diabetes medications, including insulin. Another advantage of the SGLT2 inhibitors over existing treatments is the improvement in cardiovascular risk factors, particularly in terms of reductions in blood pressure and body weight. SGLT2 inhibitors have been generally well tolerated. While more long-term safety data are required to elucidate the benefit–risk profile of SGLT2 inhibitors, the rationale for their use in type 2 diabetes therapy is strong.

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Efficacy and safety of linagliptin in type 2 diabetes subjects at high risk for renal and cardiovascular disease: a pooled analysis of six phase III clinical trials

Cardiovascular Diabetology ◽

10.1186/1475-2840-12-60 ◽

2013 ◽

Vol 12 (1) ◽

pp. 60 ◽

Cited By ~ 28

Author(s):

Maximilian von Eynatten ◽

Yan Gong ◽

Angela Emser ◽

Hans-Juergen Woerle

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Clinical Trials ◽

High Risk ◽

Pooled Analysis ◽

Phase Iii ◽

Efficacy And Safety ◽

Phase Iii Clinical Trials

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Baricitinib in rheumatoid arthritis: evidence-to-date and clinical potential

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x16687481 ◽

2017 ◽

Vol 9 (2) ◽

pp. 37-44 ◽

Cited By ~ 19

Author(s):

Bindee Kuriya ◽

Marc D. Cohen ◽

Ed Keystone

Keyword(s):

Rheumatoid Arthritis ◽

Rapid Onset ◽

Janus Kinase ◽

Phase Iii ◽

Onset Of Action ◽

Phase Iii Clinical Trials ◽

Oral Agents ◽

Number Of Patients ◽

Important Addition ◽

Clinical Potential

Biologics have changed expectation and outcomes for rheumatoid arthritis (RA). However, the optimal duration and sequence of therapy for this disease has yet to be determined. Also, a significant number of patients do not satisfactorily respond to currently available therapies. The Janus kinase (JAK) inhibitors represent a new class of therapies for RA. These drugs work uniquely by inhibiting intracellular pathways thought to be important in the pathogenesis of RA. They are available as oral agents, which is also different from the currently available biologics. Baricitinib has now been evaluated in four phase III clinical trials, and although safety concerns cannot fully be answered until the drug is studied over longer periods of time, the data to date suggest that this drug with its once daily dosing, rapid onset of action and efficacy as monotherapy represents an important addition to the RA therapeutic armamentarium. Further study and experience will better define how baricitinib will be used and by which patients.

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Cardiometabolic Disease Staging Predicts Effectiveness of Weight-Loss Therapy to Prevent Type 2 Diabetes: Pooled Results From Phase III Clinical Trials Assessing Phentermine/Topiramate Extended Release

Diabetes Care ◽

10.2337/dc17-0088 ◽

2017 ◽

Vol 40 (7) ◽

pp. 856-862 ◽

Cited By ~ 9

Author(s):

Fangjian Guo ◽

W. Timothy Garvey

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Clinical Trials ◽

Extended Release ◽

Phase Iii ◽

Cardiometabolic Disease ◽

Phase Iii Clinical Trials ◽

Disease Staging ◽

Weight Loss Therapy

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GLP-1 receptor agonists: an updated review of head-to-head clinical studies

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018821997320 ◽

2021 ◽

Vol 12 ◽

pp. 204201882199732

Author(s):

Jennifer M. Trujillo ◽

Wesley Nuffer ◽

Brooke A. Smith

Keyword(s):

Clinical Studies ◽

The United States ◽

Phase Iii ◽

Receptor Agonists ◽

Advantages And Disadvantages ◽

Phase Iii Clinical Trials ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Cardiovascular Benefit

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are attractive options for the treatment of type 2 diabetes (T2D) because they effectively lower A1C and weight while having a low risk of hypoglycemia. Some also have documented cardiovascular benefit. The GLP-1 RA class has grown in the last decade, with several agents available for use in the United States and Europe. Since the efficacy and tolerability, dosing frequency, administration requirements, and cost may vary between agents within the class, each agent may offer unique advantages and disadvantages. Through a review of phase III clinical trials studying dulaglutide, exenatide twice daily, exenatide once weekly, liraglutide, lixisenatide, semaglutide, and oral semaglutide, 14 head-to-head trials were identified that evaluated the safety and efficacy of GLP-1 RA active comparators. The purpose of this review is to provide an analysis of these trials. The GLP-1 RA head-to-head clinical studies have demonstrated that all GLP-1 RA agents are effective therapeutic options at reducing A1C. However, differences exist in terms of magnitude of effect on A1C and weight as well as frequency of adverse effects.

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The clinical potential of romosozumab for the prevention of fractures in postmenopausal women with osteoporosis

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x18775936 ◽

2018 ◽

Vol 10 (5-6) ◽

pp. 105-115 ◽

Cited By ~ 22

Author(s):

Anne Sophie Koldkjær Sølling ◽

Torben Harsløf ◽

Bente Langdahl

Keyword(s):

Postmenopausal Women ◽

Phase Iii ◽

Mineral Density ◽

Treatment Of Osteoporosis ◽

Phase Iii Clinical Trials ◽

Increased Risk ◽

Clinical Fractures ◽

Dual Action ◽

Canonical Wnt ◽

Clinical Potential

The glycoprotein sclerostin inhibits activation of the canonical Wnt pathway and thereby suppresses bone formation by inhibiting the osteoblasts. Additionally, sclerostin increases bone resorption by stimulating the production of receptor activator of nuclear factor kappa-β-ligand (RANKL). Romosozumab (ROMO) is a monoclonal antibody against sclerostin. Phase III clinical trials in postmenopausal women with osteoporosis have shown that ROMO increases bone mineral density at the lumbar spine and hip and reduces the risk of vertebral and clinical fractures in comparison with placebo. In women with severe osteoporosis, ROMO reduces the risk of vertebral, nonvertebral and clinical fractures in comparison with alendronate. ROMO is the first treatment for osteoporosis with dual action, and may become a valuable tool for improving the treatment of osteoporosis. At present, the approval of ROMO by the authorities is awaiting further investigations of a potential increased risk of cardiovascular events associated with ROMO treatment.

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