Design and evaluation of novel pyrimidine-based nucleoside analogs as antivirals: Identification of MCH-1623 as a potent broad-Spectrum antiviral candidate.

Expanding the chemical diversity of nucleosides is a vital challenge in developing antivirals. It is suggested that their volume restricts viral RdRP recognition of bases. Since the volume of substituted pyrimidines is smaller than that of purines, the pyrimidine ring can tolerate a wider range of substituents to obtain new antiviral nucleosides. Therefore, 30 nucleosides were designed based on structural analyses of the RNA-dependent RNA polymerase (RdRP) and its nucleoside complexes, using a space-filling approach. Their antiviral activities were tested against Vesicular Stomatitis Virus (VSV) and Influenza A virus strain A/Puerto Rico/8/1934 H1N1 (PR8) to identify the most promising candidate. The compound named MCH-1623 (VSV: EC50 = 13.28 μM; PR8: EC50 = 17.68 μM) was found to be the most promising. Therefore, the broad-spectrum antiviral effects of MCH-1623 were further examined, including against Human Coronavirus OC43 (HCoV-OC43, EC50 = 5.05 μM), Human Metapneumovirus (HMPV, EC50 = 9.1 μM), and Respiratory Syncytial Virus (RSV, EC50 = 34.7 μM). In vivo, MCH-1623 demonstrated effective therapeutic activity, with a 0.05 mg/kg inhalation dose significantly increasing survival in lethal H1N1-PR8 viral infections over 6 days. In a two-day mouse infection treatment experiment, MCH-1623 reduced lung H1N1-PR8 viral load and IL-6 levels and alleviated lung tissue erythema caused by the viral infection. These results suggest that MCH-1623 could be a potential drug candidate for treating various RNA virus infections, especially HMPV, for which no vaccine or specific therapy is currently available. Additionally, the activity-structure relationship analysis indicated that substituents on the pyrimidine form a rigid ring, which may serve as a useful strategy for modifying pyrimidine structures in nucleoside antiviral drugs. MCH-1623, as a lead compound, will undergo further structural modifications to develop a new class of nucleoside antivirals.