Chiral-Modified Nucleoside Analogues: From Bioactivity to Therapeutic Applications

Nucleosides are extensively employed for the development of pharmaceuticals, chemotherapeutic agents, and bioregulators. Background/Objectives: The introduction of an additional chiral functionality into a carbohydrate or heterocyclic base fragment may increase the selectivity of interactions with nucleos(t)ide-metabolizing enzymes and receptors and, in some cases, lead to more specific physiological activities. Methods: An improvement of the selectivity of nucleoside-based drugs can be achieved either by the chemical modification of a carbohydrate or a base constituent or by a combination of these two approaches. Additionally, stereospecific enzymatic cleavage of nucleos(t)ide prodrugs containing biodegradable substituents can reduce cytotoxicity and enhance bioavailability. Results: A series of enantiomerically pure nucleosides modified at the ribose or heterocyclic base were obtained by chemical and enzymatic methods. Novel antiviral or anticancer active compounds, inhibiting viral or cellular enzymes or activating cellular nucleoside kinases have been found among chemically synthesized derivatives. Some exhibit strengthened “ligand–receptor” interaction, acting on receptors of the purinergic signaling system. During recent extensive structure–activity studies, several drugs and their prototypes have been proposed for the treatment of viral infections: the 2′C-fluoromethyl derivative of sofosbuvir (anti-SARS-CoV, preclinical), VV-261 (SFTSV, phase I clinical), balapiravir (dengue, phase I clinical), mericitabine (approved drug for HCV), and lumicitabine (approved drug for RSV and HMPV). Conclusions: Modern literature data within the scope of the present review suggest that direct modification of nucleosides with various chiral functionalities can be considered as an approach to increase their efficacy, specificity and selectivity.