RESUMEN

Orthoflaviviruses, including zika (ZIKV), West Nile (WNV), and dengue (DENV) virus, induce severely debilitating infections and contribute significantly to the global disease burden, yet no clinically approved antiviral treatments exist. This review offers a comprehensive analysis of small-molecule drug development targeting orthoflaviviral infections, with a focus on NS2B-NS3 inhibition. We systematically examined clinical trials, preclinical efficacy studies, and modes of action for various viral replication inhibitors, emphasizing allosteric and orthosteric drugs inhibiting NS2B-NS3 protease with in vivo efficacy and in vitro-tested competitive NS2B-NS3 inhibitors with cellular efficacy. Our findings revealed that several compounds with in vivo preclinical efficacy failed to show clinical antiviral efficacy. NS3-NS4B inhibitors, such as JNJ-64281802 and EYU688, show promise, recently entering clinical trials, underscoring the importance of developing novel viral replication inhibitors targeting viral machinery. To date, the only NS2B-NS3 inhibitor that has undergone clinical trials is doxycycline, however, its mechanism of action and clinical efficacy as viral growth inhibitor require additional investigation. SYC-1307, an allosteric inhibitor, exhibits high in vivo efficacy, while temoporfin and methylene blue represent promising orthosteric non-competitive inhibitors. Compound 71, a competitive NS2B-NS3 inhibitor, emerges as a leading preclinical candidate due to its high cellular antiviral efficacy, minimal cytotoxicity, and favorable in vitro pharmacokinetic parameters. Challenges remain in developing competitive NS2B-NS3 inhibitors, including appropriate biochemical inhibition assays as well as the selectivity and conformational flexibility of the protease, complicating effective antiviral treatment design.

Asunto(s)

Antivirales , Proteínas no Estructurales Virales , Antivirales/farmacología , Antivirales/química , Humanos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Animales , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/uso terapéutico , Ensayos Clínicos como Asunto , Serina Endopeptidasas/metabolismo , Replicación Viral/efectos de los fármacos , Virus del Dengue/efectos de los fármacos , Virus Zika/efectos de los fármacos , Virus del Nilo Occidental/efectos de los fármacos

RESUMEN

Dengue is an important arboviral infectious disease for which there is currently no specific cure. We report gemini-like (geminoid) alkylated amphiphilic peptides containing lysines in combination with glycines or alanines (C15H31C(O)-Lys-(Gly or Ala)nLys-NHC16H33, shorthand notation C16-KXnK-C16 with X = A or G, and n = 0-2). The representatives with 1 or 2 Ala inhibit dengue protease and human furin, two serine proteases involved in dengue virus infection that have peptides with cationic amino acids as their preferred substrates, with IC50 values in the lower µM range. The geminoid C16-KAK-C16 combined inhibition of DENV2 protease (IC50 2.3 µM) with efficacy against replication of wildtype DENV2 in LLC-MK2 cells (EC50 4.1 µM) and an absence of toxicity. We conclude that the lysine-based geminoids have activity against dengue virus infection, which is based on their inhibition of the proteases involved in viral replication and are therefore promising leads to further developing antiviral therapeutics, not limited to dengue.

Asunto(s)

Antivirales , Virus del Dengue , Furina , Inhibidores de Proteasas , Replicación Viral , Antivirales/farmacología , Dengue/tratamiento farmacológico , Virus del Dengue/efectos de los fármacos , Virus del Dengue/fisiología , Furina/antagonistas & inhibidores , Humanos , Péptido Hidrolasas , Péptidos/farmacología , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos

RESUMEN

Several 2-substituted and 2,5-disubstituted piperazine-3,6-diones were synthesized starting from readily available alpha-amino acids. After activation of a lactam carbonyl via introduction of a methoxycarbonyl group onto nitrogen, this carbonyl was selectively reduced. Treatment of the resulting urethane with protic acid generated the corresponding N-acyliminium ion, which was trapped by a nucleophilic C2-side chain to provide 2,6-bridged piperazine-3-ones. Several aromatic, heteroaromatic, and nonaromatic side chains were used as pi-nucleophiles. In addition, the effect of the presence of a C5-methyl group on the stereochemical outcome of the cyclization was examined.