Multitarget Ligands and Theranostics: Sharpening the Medicinal Chemistry Sword Against Prion Diseases

Abstract

Prion diseases (PrDs) are fatal neurodegenerative disorders, for which no effective therapeutic and diagnostic tools exist. The main pathogenic event has been identified as the misfolding of a disease-associated prion protein. Nevertheless, pathogenesis seems to involve an intricate array of concomitant processes. Thus, it may be unlikely that drugs acting on single targets can effectively control PrDs. In addition, diagnosis occurs late in the disease process, by which point it is difficult to determine a successful therapeutic intervention. In this context, multitarget ligands (MTLs) and theranostic ligands (TLs) emerge for their potential to effectively cure and diagnose PrDs. In this review, we discuss the medicinal chemistry challenges of identifying novel MTLs and TLs against PrDs, and envision their impact on prion drug discovery.

Identification of novel fluorescent probes preventing PrP Sc replication in prion diseases

“…Moreover, 96 is able to bind and stain PrP Sc aggregates in infected ScN2a. The combination of this interesting anti-prion cellular profile with a fluorescence imaging behavior, and the brain permeability previously demonstrated by the class of pyrroloquinoxaline hydrazones here described [56], which support our in silico predicted brain permeability of 96, suggests that this compound could be considered as a prototypic tool the future development of diagnostic and therapeutic probes for prion diseases, as recently proposed for other classes of compounds, such as styrylquinoline against prion diseases [75] or other tools for Alzheimer's disease and related disorders [31,76,77].…”

“…Although the physiological function of PrP C still remains controversial, as well as the molecular mechanisms leading to its misfolding [4,[11][12][13][14], preventing or reducing the rate of PrP Sc conversion is currently the most widely applied therapeutic strategy against prion diseases [15][16][17]. Accordingly, a number of molecules which act by directly binding PrP C and/or blocking the conversion from PrP C to PrP Sc have been discovered by applying medicinal chemistry [18][19][20][21][22][23][24][25][26] and in silico methods [27][28][29] including repurposing strategies [30] and multi-targeting approaches [31]. Despite these efforts, effective therapies to treat prion diseases are still missing [22,[32][33][34][35].…”

From Companion Diagnostics to Theranostics: A New Avenue for Alzheimer’s Disease?

“…The literature dealing with theranostics and AD has grown steadily. It is thought that these agents could potentially offer new hope to patients and real gains for pharmaceutical and diagnostic companies. ,,,, …”

“…It is thought that these agents could potentially offer new hope to patients and real gains for pharmaceutical and diagnostic companies. 5,61,62,35,63 By analysis of the theranostic-related literature, the approaches reported to date involve two molecule classes: nanomedicines and small organic compounds. Oncology researchers have established a plethora of nanomedicines (including polymer−drug conjugates, liposomes, polymeric micelles, and inorganic nanoparticles) with distinctive chemical compositions and physical properties.…”