Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy

Abstract

Rationally designed multi-target drugs (also termed multimodal drugs, network therapeutics, or designed multiple ligands) have emerged as an attractive drug discovery paradigm in the last 10–20 years, as potential therapeutic solutions for diseases of complex etiology and diseases with significant drug-resistance problems. Such agents that modulate multiple targets simultaneously are developed with the aim of enhancing efficacy or improving safety relative to drugs that address only a single target or to combinations of single-target drugs. Although this strategy has been proposed for epilepsy therapy >25 years ago, to my knowledge, only one antiseizure medication (ASM), padsevonil, has been intentionally developed as a single molecular entity that could target two different mechanisms. This novel drug exhibited promising effects in numerous preclinical models of difficult-to-treat seizures. However, in a recent randomized placebo-controlled phase IIb add-on trial in treatment-resistant focal epilepsy patients, padsevonil did not separate from placebo in its primary endpoints. At about the same time, a novel ASM, cenobamate, exhibited efficacy in several randomized controlled trials in such patients that far surpassed the efficacy of any other of the newer ASMs. Yet, cenobamate was discovered purely by phenotype-based screening and its presumed dual mechanism of action was only described recently. In this review, I will survey the efficacy of single-target vs. multi-target drugs vs. combinations of drugs with multiple targets in the treatment and prevention of epilepsy. Most clinically approved ASMs already act at multiple targets, but it will be important to identify and validate new target combinations that are more effective in drug-resistant epilepsy and eventually may prevent the development or progression of epilepsy.

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

“…However, as shown in Figure 4 , epileptogenesis is a complex multifactorial process, so it seems unlikely that affecting neuroinflammation alone will be sufficient to halt this process. We have proposed previously that multi-targeted cocktails of drugs may provide a more effective strategy for epilepsy prevention after brain insults ( Löscher, 2021 ; Löscher and Klein, 2021b ). Proof of concept of this strategy has been achieved for the intrahippocampal kainate mouse model of TLE ( Schidlitzki et al, 2020 ; Welzel et al, 2021 ).…”

OptNCMiner: A deep learning approach for the discovery of natural compounds modulating disease-specific multi-targets

“…The unique scaffolds and structural motifs of NCs enable interactions with multiple target proteins to elicit diverse biological activities (9). In the past few decades, the paradigm of drug discovery has shifted from 'one target, one disease' to 'multi-target' or 'multimodal' drug discovery, especially for diseases with complex etiologies or drug resistance issues (10). Such multi-target modulating drugs have been expected to improve safety issues and enhance clinical e cacy compared to single-target drugs (11)(12)(13).…”

New Phenylglycinamide Derivatives with Hybrid Structure as Candidates for New Broad-Spectrum Anticonvulsants

“…Notably, the transition from the single-target to the multi-target concept is observed predominantly in the case of neurodegenerative diseases (i.e., Alzheimer’s and Parkinson’s), depression, diabetes, metabolic and inflammatory diseases, cancer, as well as other neurological disorders such as epilepsy and neuropathic pain [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Importantly, the current literature data indicate higher clinical efficacy of ASDs with a multimodal mechanism of action vs. drugs that act on a single target, such as ASD with superior efficacy valproic acid (VPA) [ 13 ]. It should be also stressed that combining different molecular mechanisms is potentially beneficial in the treatment of diseases with a high risk of drug resistance, including epilepsy, as well as infectious diseases that are caused by different pathogens (i.e., bacteria, fungi, etc.)…”