Drug discovery strategies for acute radiation syndrome

Abstract

Introduction: There are at the minimum two major, quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach. Area covered: The authors discuss, herein, the need for developing radiation countermeasure agents for various sub-syndromes of acute radiation syndromes (ARS) following TBDD and PBDD approaches. With time and continuous advances in radiation countermeasure drug development research, the expectation is to have multiple radiation countermeasure agents for each sub-syndrome made available to radiation exposed victims. Expert opinion: The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized. In the future, an improved drug development strategy might be a 'hybrid' strategy that is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS.

How necessary are animal models for modern drug discovery?

“…The former, TBDD, is referred to commonly as the molecular approach, while the latter, PBDD, is referred to as the physiology-based or empirical approach [24,25]. In a PBDD approach, the animal models play a more important role, as pharmacological actions are first identified in cells, tissues, or animal models without knowledge of specific molecular targets [26]. The PBDD approach is reemerging as an alternative platform for drug discovery and is more dependent on studies conducted in animals.…”

Metabolomics-based predictive biomarkers of radiation injury and countermeasure efficacy: current status and future perspectives

“…These three radiation medical countermeasures were in clinical use for several decades for other indications prior to their approval by the FDA as radiomitigators for H-ARS. No additional, new chemical agent has yet been FDA-approved as a radiation countermeasure for ARS [78] .…”

Medical countermeasures for radiation induced health effects: report of an Interagency Panel Session held at the NASA Human Research Program Investigator’s Workshop, 26 January 2017

“…BARDA focuses on MCM candidates that are ready for advanced development. Due to the complex spectrum of injuries that are anticipated to include combined injuries of acute radiation exposure, trauma, and thermal burn, treatment is expected to require a polypharmacy approach (Yoo et al 2014;Singh et al 2019). Over the years, BARDA has evolved its focus away from organ-centric syndromes to focus on more pathophysiological processes involved in radiation injury.…”