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J Med Chem ; 65(1): 876-884, 2022 01 13.
Article in English | MEDLINE | ID: covidwho-1606194


Coronavirus disease 2019 (COVID-19) pandemic, a global health threat, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 papain-like cysteine protease (PLpro) was recognized as a promising drug target because of multiple functions in virus maturation and antiviral immune responses. Inhibitor GRL0617 occupied the interferon-stimulated gene 15 (ISG15) C-terminus-binding pocket and showed an effective antiviral inhibition. Here, we described a novel peptide-drug conjugate (PDC), in which GRL0617 was linked to a sulfonium-tethered peptide derived from PLpro-specific substrate LRGG. The EM-C and EC-M PDCs showed a promising in vitro IC50 of 7.40 ± 0.37 and 8.63 ± 0.55 µM, respectively. EC-M could covalently label PLpro active site C111 and display anti-ISGylation activities in cellular assays. The results represent the first attempt to design PDCs composed of stabilized peptide inhibitors and GRL0617 to inhibit PLpro. These novel PDCs provide promising opportunities for antiviral drug design.

Aniline Compounds/chemistry , Antiviral Agents/metabolism , Benzamides/chemistry , Coronavirus Papain-Like Proteases/metabolism , Drug Design , Naphthalenes/chemistry , Peptides/chemistry , SARS-CoV-2/enzymology , Aniline Compounds/metabolism , Aniline Compounds/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzamides/metabolism , Benzamides/pharmacology , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Cell Line , Cell Survival/drug effects , Coronavirus Papain-Like Proteases/chemistry , Cytokines/chemistry , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Naphthalenes/metabolism , Naphthalenes/pharmacology , SARS-CoV-2/isolation & purification , Ubiquitins/chemistry
Molecules ; 26(16)2021 Aug 19.
Article in English | MEDLINE | ID: covidwho-1376915


G-quadruplexes (G4s) are higher-order supramolecular structures, biologically important in the regulation of many key processes. Among all, the recent discoveries relating to RNA-G4s, including their potential involvement as antiviral targets against COVID-19, have triggered the ever-increasing need to develop selective molecules able to interact with parallel G4s. Naphthalene diimides (NDIs) are widely exploited as G4 ligands, being able to induce and strongly stabilize these structures. Sometimes, a reversible NDI-G4 interaction is also associated with an irreversible one, due to the cleavage and/or modification of G4s by functional-NDIs. This is the case of NDI-Cu-DETA, a copper(II) complex able to cleave G4s in the closest proximity to the target binding site. Herein, we present two original Cu(II)-NDI complexes, inspired by NDI-Cu-DETA, differently functionalized with 2-(2-aminoethoxy)ethanol side-chains, to selectively drive redox-catalyzed activity towards parallel G4s. The selective interaction toward parallel G4 topology, controlled by the presence of 2-(2-aminoethoxy)ethanol side chains, was already firmly demonstrated by us using core-extended NDIs. In the present study, the presence of protonable moieties and the copper(II) cavity, increases the binding affinity and specificity of these two NDIs for a telomeric RNA-G4. Once defined the copper coordination relationship and binding constants by competition titrations, ability in G4 stabilization, and ROS-induced cleavage were analyzed. The propensity in the stabilization of parallel topology was highlighted for both of the new compounds HP2Cu and PE2Cu. The results obtained are particularly promising, paving the way for the development of new selective functional ligands for binding and destructuring parallel G4s.

Coordination Complexes/chemistry , Copper/chemistry , G-Quadruplexes , Imides/chemistry , Naphthalenes/chemistry , Binding Sites , DEET/chemistry , Ligands , Oxidation-Reduction , Polyethylene Glycols/chemistry , Structure-Activity Relationship