Article
Cardiac & Cardiovascular Systems
Scott D. Solomon, Brian L. Claggett, Zi Michael Miao, Rafael Diaz, G. Michael Felker, John J. McMurray, Marco Metra, Ramon Corbalan, Gerasimos Filippatos, Assen R. Goudev, Viatcheslav Mareev, Pranas Serpytis, Thomas Suter, Mehmet B. Yilmaz, Faiez Zannad, Stuart Kupfer, Stephen B. Heitner, Fady Malik, John R. Teerlink
Summary: In the GALACTIC-HF study, the influence of atrial fibrillation on the effectiveness of omecamtiv mecarbil was explored. The study found that patients with atrial fibrillation derived less benefit from omecamtiv mecarbil treatment, especially those who were also receiving digoxin.
EUROPEAN HEART JOURNAL
(2022)
Article
Pharmacology & Pharmacy
Ashit Trivedi, Cheng-Pang Hsu, Pegah Jafarinasabian, Bianca Terminello, Hanze Zhang, Stephen Flach, Samuel Israel, Ashley Brooks, Hongqi Xue, Borje Darpo, Siddique Abbasi, Sandeep Dutta, Edward Lee
Summary: The study found that Omecamtiv mecarbil (OM) at therapeutic concentrations has no clinically relevant effect on ECG parameters and does not affect the QTc interval significantly up to a plasma concentration of approximately 800 ng/mL. No serious adverse events leading to discontinuation from the study were observed.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Arnold Peter Raduly, Attila Toth, Fruzsina Sarkany, Balazs Horvath, Norbert Szentandrassy, Peter P. Nanasi, Zoltan Csanadi, Istvan Edes, Zoltan Papp, Attila Borbely
Summary: This study aimed to compare the effects of different mechanisms of calcium-sensitizing positive inotropic agents (OM, EMD, and Levo) on cardiomyocytes. The results showed that OM exerted its positive inotropic effect by prolonging systolic contraction and increasing calcium sensitivity. In contrast, EMD and Levo exerted positive inotropic effects through different mechanisms. These findings have important implications for the further development of drugs for treating heart failure.
Article
Pharmacology & Pharmacy
Ashit Trivedi, Mia Mackowski, Pegah Jafarinasabian, Hanze Zhang, Stephen Flach, Bianca Terminello, Ajay Bhatia, Sandeep Dutta, Edward Lee
Summary: The study aimed to determine the bioavailability of two OM minitablet formulations relative to the adult matrix MR formulation. Results showed that the slow-release and fast-release minitablets demonstrated bioavailability similar to the adult matrix MR formulation.
CLINICAL DRUG INVESTIGATION
(2021)
Article
Cardiac & Cardiovascular Systems
Gabor A. Fulop, Attila Olah, Tamas Csipo, Arpad Kovacs, Robert Porszasz, Roland Veress, Balazs Horvath, Laszlo Nagy, Beata Bodi, Miklos Fagyas, Solveig Lind Helgadottir, Viktor Banhegyi, Bela Juhasz, Mariann Bombicz, Daniel Priksz, Peter Nanasi, Bela Merkely, Istvan Edes, Zoltan Csanadi, Zoltan Papp, Tamas Radovits, Attila Toth
Summary: Omecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility, but may have previously unrecognized side effects. Concentration-dependent improvements in cardiac function were observed with OM, although higher concentrations were associated with hypotension and diastolic dysfunction.
BASIC RESEARCH IN CARDIOLOGY
(2021)
Article
Cardiac & Cardiovascular Systems
John R. Teerlink, Rafael Diaz, G. Michael Felker, John J. McMurray, Marco Metra, Scott D. Solomon, Tor Biering-Sorensen, Michael Boehm, Diana Bonderman, James C. Fang, David E. Lanfear, Mayanna Lund, Shin-Ichi Momomura, Eileen O'Meara, Piotr Ponikowski, Jindrich Spinar, Jose H. Flores-Arredondo, Brian L. Claggett, Stephen B. Heitner, Stuart Kupfer, Siddique A. Abbasi, Fady Malik
Summary: In heart failure patients, omecamtiv mecarbil produces greater therapeutic benefit as baseline ejection fraction decreases, particularly in patients with lower baseline EF.
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Ashit Trivedi, Rajneet K. Oberoi, Pegah Jafarinasabian, Hanze Zhang, Marintan Spring, Stephen Flach, Siddique Abbasi, Sandeep Dutta, Edward Lee
Summary: The study showed that there was no clinically relevant effect of Omecamtiv mecarbil (OM) on the pharmacokinetics of metformin in healthy subjects. Co-administration of OM with metformin did not significantly alter the pharmacokinetic parameters of metformin compared to metformin alone.
CLINICAL DRUG INVESTIGATION
(2021)
Article
Medicine, Research & Experimental
Yusheng Qu, BaoXi Gao, Ziva Arimura, Mei Fang, Hugo M. Vargas
Summary: Omecamtiv mecarbil (OM) is a myosin activator developed for treating heart failure. Studies showed that OM had minimal impact on the heart in a series of experiments, indicating no delay in ventricular repolarization.
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
(2021)
Article
Cardiac & Cardiovascular Systems
Marco Metra, Matteo Pagnesi, Brian L. Claggett, Rafael Diaz, G. Michael Felker, John J. V. McMurray, Scott D. Solomon, Diana Bonderman, James C. Fang, Candida Fonseca, Eva Goncalvesova, Jonathan G. Howlett, Jing Li, Eileen O'Meara, Zi Michael Miao, Siddique A. Abbasi, Stephen B. Heitner, Stuart Kupfer, Fady I. Malik, John R. Teerlink
Summary: The study shows that Omecamtiv mecarbil is more effective in patients with lower systolic blood pressure in improving heart failure outcomes, with good tolerability.
EUROPEAN HEART JOURNAL
(2022)
Article
Chemistry, Physical
Ananya Chakraborti, Jil C. Tardiff, Steven D. Schwartz
Summary: The study investigated the influence of the positive inotrope Omecamtiv mecarbil (OM) on the recovery stroke of cardiac myosin, as well as its effects in the presence of genetic cardiomyopathic mutations. The study utilized metadynamics and transition path sampling to gain insights into the dynamics and mechanism of ATP hydrolysis in the presence of OM. Understanding the effects of OM is crucial for its potential use in the treatment of cardiac disease.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Biology
Aaron Snoberger, Bipasha Barua, Jennifer L. Atherton, Henry Shuman, Eva Forgacs, Yale E. Goldman, Donald A. Winkelmann, E. Michael Ostap
Summary: The study revealed a novel mechanism, showing that the R712L mutation decreases the working stroke of myosin, while OM is able to rescue this inhibition, providing insights into the pathogenesis of HCM.
Article
Medicine, Research & Experimental
Ashit Trivedi, Winnie Sohn, Priyanka Kulkarni, Pegah Jafarinasabian, Hanze Zhang, Marintan Spring, Stephen Flach, Siddique Abbasi, Jan Wahlstrom, Edward Lee, Sandeep Dutta
Summary: OM, a novel cardiac myosin activator, is a weak inhibitor of BCRP substrates, as observed in a clinical study of single dose OM.
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
(2021)
Article
Physiology
Ranganath Mamidi, Joshua B. Holmes, Chang Yoon Doh, Katherine L. Dominic, Nikhil Madugula, Julian E. Stelzer
Summary: This study investigated the effects of OM on force generation and cross-bridge kinetics in myocardial preparations with reduced cMyBPC phosphorylation. The results showed significant differences in the effects of OM between WT and SA myocardial preparations, suggesting an interplay between OM and XB behavior which may alter the cardiac response to 13-adrenergic stimulation.
JOURNAL OF GENERAL PHYSIOLOGY
(2021)
Article
Medicine, General & Internal
John R. Teerlink, Rafael Diaz, G. Michael Felker, John J. V. McMurray, Marco Metra, Scott D. Solomon, Kirkwood F. Adams, Inder Anand, Alexandra Arias-Mendoza, Tor Biering-Sorensen, Michael Bohm, Diana Bonderman, John G. F. Cleland, Ramon Corbalan, Maria G. Crespo-Leiro, Ulf Dahlstrom, Luis E. Echeverria, James C. Fang, Gerasimos Filippatos, Candida Fonseca, Eva Goncalvesova, Assen R. Goudev, Jonathan G. Howlett, David E. Lanfear, Jing Li, Mayanna Lund, Peter Macdonald, Viacheslav Mareev, Shin-ichi Momomura, Eileen O'Meara, Alexander Parkhomenko, Piotr Ponikowski, Felix J. A. Ramires, Pranas Serpytis, Karen Sliwa, Jindrich Spinar, Thomas M. Suter, Janos Tomcsanyi, Hans Vandekerckhove, Dragos Vinereanu, Adriaan A. Voors, Mehmet B. Yilmaz, Faiez Zannad, Lucie Sharpsten, Jason C. Legg, Claire Varin, Narimon Honarpour, Siddique A. Abbasi, Fady I. Malik, Christopher E. Kurtz
Summary: Among patients with heart failure and reduced ejection fraction, those who received omecamtiv mecarbil had a lower incidence of heart-failure events or cardiovascular death compared to those who received placebo over a median of 22 months.
NEW ENGLAND JOURNAL OF MEDICINE
(2021)
Article
Pharmacology & Pharmacy
Ashit Trivedi, Jan Wahlstrom, Mia Mackowski, Sandeep Dutta, Edward Lee
Summary: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator being developed for the treatment of heart failure, primarily cleared through metabolism by the CYP4 family. The major metabolites recovered in urine and feces were M3 and M4, with high bioavailability of 93.5%.
DRUG METABOLISM AND DISPOSITION
(2021)
Article
Biochemistry & Molecular Biology
Osha Roopnarine, David D. Thomas
Summary: The study found that ten actin-binding compounds affect the interaction between cardiac myosin subfragment 1 (S1) and pyrene-labeled F-actin (PFA), increasing ATP affinity for actin-bound myosin and slowing the transition of actin-myosin interaction in the early ATPase cycle. This work elucidates the mechanisms of action for these compounds, providing valuable insights for potential treatments of hypercontractile forms of cardiomyopathy and future drug discovery efforts for heart failure.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Ang Li, Samantha L. Yuen, Daniel R. Stroik, Evan Kleinboehl, Razvan L. Cornea, David D. Thomas
Summary: The study demonstrates that DWORF enhances SERCA2a function by competing with PLB for binding, potentially offering a novel therapeutic approach for heart failure.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Abir Majumdar, David J. Burban, Joseph M. Muretta, Andrew R. Thompson, Tiffany A. Engel, Damien M. Rasmussen, Manu V. Subrahmanian, Gianluigi Veglia, David D. Thomas, Nicholas M. Levinson
Summary: CDKs are master regulators of the eukaryotic cell cycle, requiring regulatory phosphorylation and cyclin binding for activation. The study explores the activation process of Cdk2 and its allosteric coupling with different regulators, revealing differences between Cdk2 and Cdk4 in allosteric wiring and substrate specificity.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Biology
Cristina Olivieri, Caitlin Walker, Adak Karamafrooz, Yingjie Wang, V. S. Manu, Fernando Porcelli, Donald K. Blumenthal, David D. Thomas, David A. Bernlohr, Simon M. Sandford, Susan S. Taylor, Gianluigi Veglia
Summary: The fusion of the dynamic J-domain to PKA-C disrupts the internal allosteric network, causing attenuation of nucleotide/PKI binding cooperativity. This reduced allosteric cooperativity alters specific recognitions and interactions between substrates and regulatory partners, contributing to dysregulation exhibited by PKA-C-DNAJB1.
COMMUNICATIONS BIOLOGY
(2021)
Article
Biology
Daniel K. Weber, U. Venkateswara Reddy, Songlin Wang, Erik K. Larsen, Tata Gopinath, Martin B. Gustavsson, Razvan L. Cornea, David D. Thomas, Alfonso De Simone, Gianluigi Veglia
Summary: Phospholamban (PLN) regulates cardiac Ca2+ transport response by phosphorylation or increased Ca2+ concentration, disrupting inhibitory contacts on the SERCA binding interface and enhancing Ca2+ transport. This study sheds light on the signal transduction mechanism operated by posttranslationally modified bitopic membrane proteins, addressing longstanding questions about SERCA regulation.
Correction
Biology
Cristina Olivieri, Caitlin Walker, Adak Karamafrooz, Yingjie Wang, V. S. Manu, Fernando Porcelli, Donald K. Blumenthal, David D. Thomas, David A. Bernlohr, Sanford M. Simon, Susan S. Taylor, Gianluigi Veglia
COMMUNICATIONS BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Thomas A. Bunch, Piyali Guhathakurta, Victoria C. Lepak, Andrew R. Thompson, Rhye-Samuel Kanassatega, Anna Wilson, David D. Thomas, Brett A. Colson
Summary: This study identified small-molecule inhibitors that affect the binding between cMyBP-C and actin, providing potential targets for heart failure drugs that mimic phosphorylation or disrupt interactions with actin/myosin. The fluorescence lifetime assay allowed for the detection of pharmacologically active compounds that interfere with cMyBP-C-actin binding. This validated high-throughput screen focused on cMyBP-C, a regulator of cardiac muscle contractility and a key factor in heart failure, for the first time.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Sami Chu, Joseph M. Muretta, David D. Thomas
Summary: The study aimed to test whether the IHM structure is the structural basis for the SRX state, and the results indicated that the IHM structure is sufficient but not necessary to produce the SRX kinetic state.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Mark D. Rustad, Osha Roopnarine, Razvan L. Cornea, David D. Thomas
Summary: Insufficient activity of SERCA, the integral transmembrane Ca2+ pump, contributes significantly to heart failure, a leading cause of death worldwide. The novel DWORF micropeptide has been identified as a muscle-specific SERCA effector that can reverse the inhibitory effects of PLB and activate SERCA independently. However, the structural basis for these functions has not yet been determined.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Philip A. A. Bidwell, Samantha L. L. Yuen, Ji Li, Kaja Berg, Robyn T. T. Rebbeck, Courtney C. C. Aldrich, Osha Roopnarine, Razvan L. L. Cornea, David D. D. Thomas
Summary: The sarco/endoplasmic reticulum Ca-ATPase (SERCA) is a critical ion pump for muscle function, and increasing its activity could alleviate muscle dysfunction. Through high-throughput screening, several compounds were discovered that can activate SERCA and improve calcium uptake in both cardiac and skeletal muscles.
Article
Biochemistry & Molecular Biology
Bengt Svensson, Florentin R. Nitu, Robyn T. Rebbeck, Lindsey M. Mcgurran, Tetsuro Oda, David D. Thomas, Donald M. Bers, Razvan L. Cornea
Summary: Current studies have shown that Ca2+ leakage from cardiomyocyte sarcoplasmic reticulum through hyperactive resting cardiac ryanodine receptor channels (RyR2) has a pro-arrhythmic effect. An exogenous peptide (DPc10) binding promotes leaky RyR2 in cardiomyocytes and reports on the endogenous state. Conversely, binding of calmodulin (CaM) inhibits RyR2 leak and low CaM affinity is indicative of leaky RyR2. These findings have led to the development of a FRET biosensor for drug discovery targeting RyR2.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Elisa Bovo, Robyn T. Rebbeck, Osha Roopnarine, David D. Thomas, Razvan L. Cornea, Aleksey Zima
Summary: This study reveals that Compound 6 exhibits promising characteristics that can improve intracellular Ca2+ dynamics by selectively enhancing SERCA2a Ca2+ uptake.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Veterinary Sciences
Joseph M. Autry, Bengt Svensson, Samuel F. Carlson, Zhenhui Chen, Razvan L. Cornea, David D. Thomas, Stephanie J. Valberg
Summary: The enzymatic activity of SERCA from horse muscle was analyzed, and it was found that horse SR vesicles have a higher Ca2+ transport rate and increased luminal Ca2+ stores compared to rabbit SR vesicles. This may be due to a reduced SLN inhibition of SERCA and abundant expression of CASQ in horse myofibers.
VETERINARY SCIENCES
(2021)
Article
Biochemical Research Methods
Adak Karamafrooz, Jack Brennan, David D. Thomas, Laurie L. Parker
Summary: The DNAJB1-PRKACA fusion is a signature genetic event of FL-HCC, potentially upregulating oncogenic pathways through redirecting substrate recognition. By integrating cell-based and in vitro phosphoproteomics, substrates directly targeted by PKA and J-PKA(ca) were identified, with inhibitors showing differential effects on substrates in the presence of the fusion protein.
JOURNAL OF PROTEOME RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Robyn T. Rebbeck, Anna K. Andrick, Sarah A. Denha, Bengt Svensson, Piyali Guhathakurta, David D. Thomas, Thomas S. Hays, Adam W. Avery
Summary: This study established a high-throughput screening method for discovering potential disrupters of the interaction between mutant beta-III-spectrin ABD and actin in live cells, showing its effectiveness.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)