UCI-1

In this study, we performed the hit-to-lead optimization of a SARS-CoV-2 Mpro diazepane hit (identified by computational methods in a previous work) by combining computational simulations with high-throughput medicinal chemistry (HTMC). Leveraging the 3D structural information of Mpro, we refined the original hit by targeting the S1 and S2 binding pockets of the protein. Additionally, we identified a novel exit vector pointing toward the S1' pocket, which significantly enhanced the binding affinity. This strategy enabled us to transform, rapidly with a limited number of compounds synthesized, a 14 μM hit into a potent 16 nM lead compound, for which key pharmacological properties were subsequently evaluated. This result demonstrated that combining computational technologies such as machine learning, molecular docking, and molecular dynamics simulation with HTMC can efficiently accelerate hit identification and subsequent lead generation.

Despite effective vaccines and treatments for COVID-19, clinical burden persists. An unmet need exists for additional effective agents with safety profiles allowing use across a broad population. Ibuzatrelvir is an orally bioavailable SARS-CoV-2 Mpro inhibitor with demonstrated in vitro antiviral activity and low potential for safety concerns, including drug–drug interactions.

This phase 2b, double-blind, randomized clinical trial enrolled US adults aged 18 to <65 years with symptomatic COVID-19 and no risk factors for severe disease. Participants were randomized 1:1:2:2 to receive 100, 300, or 600 mg ibuzatrelvir or placebo orally twice daily for 5 days. Nasopharyngeal specimens were collected on days 1 (baseline), 3, 5, 10, 14, and 21; adverse events (AEs) were recorded through day 33. The primary end point was change in SARS-CoV-2 RNA level (viral load [VL]) from baseline to day 5 among participants with baseline VL ≥4 log10 copies/mL.

Of 240 enrollees, 237 received ≥1 dose; 199 were included in the primary analysis. Placebo-adjusted least squares mean (80% confidence interval) change from baseline in VL (log10 copies/mL) at day 5 was significant across all doses: 100 mg, ‒0.7 (‒1.1 to ‒0.3) log10 copies/mL, P = .02; 300 mg, ‒0.8 (‒1.3 to ‒0.3), P = .01; and 600 mg, ‒1.2 (‒1.5 to ‒0.8), P < .0001. AEs occurred in similar percentages of participants across groups. No deaths from any cause or treatment-related serious AEs occurred through day 33, and no participants reported dysgeusia.

All 3 ibuzatrelvir doses were associated with robust antiviral activity and an acceptable safety profile, supporting continued clinical development.

NCT05799495.