Strategies for targeting the cardiac sarcomere: avenues for novel drug discovery

Abstract

Introduction: Heart failure remains one of the largest clinical challenges in the United States. Researchers have continually searched for more effective heart failure treatments that target the cardiac sarcomere but have found few successes despite numerous expensive cardiovascular clinical trials. Among many reasons, the high failure rate of cardiovascular clinical trials may be partly due to incomplete characterization of a drug candidate's complex interaction with cardiac physiology.Areas covered: In this review, the authors address the issue of preclinical cardiovascular studies of sarcomere-targeting heart failure therapies. The authors consider inherent tradeoffs made between mechanistic transparency and physiological fidelity for several relevant preclinical techniques at the atomic, molecular, heart muscle fiber, whole heart, and whole-organism levels. Thus, the authors suggest a comprehensive, bottom-up approach to preclinical cardiovascular studies that fosters scientific rigor and hypothesis-driven drug discovery.Expert opinion: In the authors' opinion, the implementation of hypothesis-driven drug discovery practices, such as the bottom-up approach to preclinical cardiovascular studies, will be imperative for the successful development of novel heart failure treatments. However, additional changes to clinical definitions of heart failure and current drug discovery culture must accompany the bottom-up approach to maximize the effectiveness of hypothesis-driven drug discovery.

Keywords: Drug discovery; biophysical measurements; cross-bridge kinetics; heart failure; in vivo function; sarcomere-based therapy; solution-based chemistry.

Figure 1.

Omecamtiv mecarbil (OM) was docked to the cardiac myosin S1 fragment in the pre-powerstroke state crystal structure (PDB ID 5N69) using the Genetic Lamarckian algorithm in AutoDock. The OM pose from the crystal structure (blue) and the predicted pose from the example docking experiment (red) differs by RMSD = 6.364 Å, calculated using PyMOL’s rms_cur matchmaker command (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC.). The predicted affinity via docking was 0.23 μM.

Figure 2:

(A) Experimental setup consisting of a motor arm (a) and force transducer (b) placed within the chamber in which solutions containing various amounts of Ca²⁺ and drugs can be loaded. (B) A multicellular detergent-skinned cardiac muscle preparation (a) is fixed in between the motor arm and a force transducer troughs (b) and secured using polydioxanone pins (violet-colored) and nylon loops (black colored). (C) Shown is a magnified image (40x) of a detergent-skinned cardiac muscle preparation secured on either end as shown in panel B.