Abstract
ABSTRACTAlthough members of the Flaviviridae display high incidence, morbidity, and mortality rates, the development of specific antiviral drugs for each virus is unlikely. Cyclophilins, a family of host peptidyl-prolyl cis-trans isomerases (PPIases), play a pivotal role in the life cycles of many viruses and therefore represent an attractive target for broad-spectrum antiviral development. We report here the pangenotypic anti-hepatitis C virus (HCV) activity of a small-molecule cyclophilin inhibitor (SMCypI). Mechanistic and modeling studies revealed that the SMCypI bound to cyclophilin A in competition with cyclosporine (CsA), inhibited its PPIase activity, and disrupted the CypA-nonstructural protein 5A (NS5A) interaction. Resistance selection showed that the lead SMCypI hardly selected amino acid substitutions conferring low-level or no resistance in vitro. Interestingly, the SMCypI selected D320E and Y321H substitutions, located in domain II of the NS5A protein. These substitutions were previously associated with low-level resistance to cyclophilin inhibitors such as alisporivir. Finally, the SMCypI inhibited the replication of other members of the Flaviviridae family with higher 50% effective concentrations (EC50s) than for HCV. Thus, because of its chemical plasticity and simplicity of synthesis, our new family of SMCypIs represents a promising new class of drugs with the potential for broad-spectrum anti-Flaviviridae activity as well as an invaluable tool to explore the role of cyclophilins in viral life cycles.
Highlights
Urbanization, human migrations, and climate changes facilitate the emergence or reemergence of a large number of viruses causing unexpected illnesses and epidemics, while the capacity to identify and control emerging diseases is limited in poorer regions where many of them have their origin [1]
Anti-hepatitis C virus (HCV) drug research highlighted the antiviral potential of Cyp inhibition through the clinical development of nonimmunosuppressive derivatives of CsA
Drug discovery approach using nucleic magnetic resonance, X-ray crystallography, and structure-based compound optimization to generate a new family of nonpeptidic, small-molecule cyclophilin inhibitors (SMCypIs) unrelated to CsA, with broad cyclophilin in vitro peptidyl-prolyl cis-trans isomerases (PPIases)-inhibitory activity and antiviral activity against HCV, HIV, and coronaviruses [18]
Summary
Urbanization, human migrations, and climate changes facilitate the emergence or reemergence of a large number of viruses causing unexpected illnesses and epidemics, while the capacity to identify and control emerging diseases is limited in poorer regions where many of them have their origin [1]. No antiviral drugs are available so far to cure infections caused by arthropod-borne members of the Flaviviridae family, despite their global public health importance. During the past 10 years, two different types of antiviral agents, including DAAs and host-targeting antiviral (HTA) agents, have been developed for the treatment of HCV infection. Its development was halted following the report of seven cases of acute pancreatitis, including a lethal one [7] These events were independent from Cyp inhibition, most likely due to ALV-induced hypertriglyceridemia that potentiated the pancreatic toxicity of interferon alpha that was part of the combination regimens. Our SMCypIs displayed antiviral effectiveness against HCV and against HIV and coronaviruses, suggesting, together with data reported in the literature, that they could act as broad-spectrum antiviral agents, effective against a number of different viruses from different virus families. The present study aims at characterizing the anti-HCV activity of the new family of SMCypIs, unraveling their molecular antiviral mechanism, and evaluating their spectrum of anti-Flaviviridae activity
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