ABSTRACT
Peptides can be inhibitors and substrates of proteases. The present study describes the inhibitor- vs. substrate-like properties of peptidic ligands of dengue protease which were designed to provide insight into their binding modes. Of particular interest was the localization of the cleavable peptide bond and the placement of hydrophobic elements in the binding site. The findings provide clues for the design of covalent inhibitors in which electrophilic functional groups bind to the catalytic serine, and in addition for the development of inhibitors that are less basic than the natural substrate and therefore have an improved pharmacokinetic profile. We observed a tendency of basic elements to favor a substrate-like binding mode, whereas hydrophobic elements decrease or eliminate enzymatic cleavage. This indicates a necessity to include basic elements which closely mimic the natural substrates into covalent inhibitors, posing a challenge from the chemical and pharmacokinetic perspective. However, hydrophobic elements may offer opportunities to develop non-covalent inhibitors with a favorable ADME profile and potentially improved target-binding kinetics.
Subject(s)
Peptide Hydrolases/metabolism , Peptides/pharmacology , Protease Inhibitors/pharmacology , Chromatography, Liquid , Dose-Response Relationship, Drug , HIV/enzymology , Hepacivirus/enzymology , Hydrophobic and Hydrophilic Interactions , Ligands , Mass Spectrometry , Molecular Structure , Peptides/chemical synthesis , Peptides/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Nucleoside and nucleotide analogues are structurally similar antimetabolites and are promising small-molecule chemotherapeutic agents against various infectious DNA and RNA viruses. To date, these analogues have not been documented in-depth as anti-human immunodeficiency virus (HIV) and anti-hepatitis virus agents, these are at various stages of testing ranging from pre-clinical, to those withdrawn from trials, or those that are approved as drugs. Hence, in this review, the importance of these analogues in tackling HIV and hepatitis virus infections is discussed with a focus on the viral genome and the mechanism of action of these analogues, both in a mutually exclusive manner and their role in HIV/hepatitis coinfection. This review encompasses nucleoside and nucleotide analogues from 1987 onwards, starting with the first nucleoside analogue, zidovudine, and going on to those in current clinical trials and even the drugs that have been withdrawn. This review also sheds light on the prospects of these nucleoside analogues in clinical trials as a treatment option for the COVID-19 pandemic.