China's self-developed oral antiviral drugs are expected to enter the clinic in the second half of the year

Beijing, January 25 – The Global Health Drug Discovery Center (GHDDI) announced that GDI-4405, a preclinical candidate drug molecule targeting the novel coronavirus 3CL protease, has accelerated the promotion of a number of clinical trial application studies and drug production, and is expected to enter the clinic in the second half of 2022. Multiple experiments have shown that GDI-4405 can effectively inhibit the replication of the new crown virus, and perform well in bioavailability and safety, which is expected to become a special drug to combat the ever-evolving covid-19 epidemic.

"As the global COVID-19 pandemic continues to develop, there is an urgent need for more effective and convenient oral anti-COVID-19 drugs to meet global access to drugs. To this end, I am proud of the team's hard work and breakthroughs, and I am grateful to our sponsors, Tsinghua University, the Bill & Melinda Gates Foundation, and the Beijing Municipal Government, as well as the continued support of partners such as the Tencent Foundation. The clinical drug candidate molecule GDI-4405 identified by us exhibited stronger antiviral activity than Pfizer's approved drug Paxlovid in a series of in vitro experiments such as inhibitory of enzymatic activity of the recombinant SARS-CoV-2 3CL protein, inhibition of SARS-CoV-2 live virus infected by human respiratory epithelial cells, and a series of in vitro experiments against Delta variant virus. In rat and cynobivorous monkey animal experiments, GDI-4405 also showed superior bioavailability and exposure. In animal toxicology evaluation experiments, GDI-4405 showed good safety. Its production cost is also better than Pfizer's NEW crown drug Paxlovid," said Ding Sheng, director of the Global Health Drug Research and Development Center (GHDDI) and dean of the School of Pharmacy at Tsinghua University, "Which will further promote the global small molecule oral COVID-19 drug research and development process as an effective supplement to vaccines." ”

In response to the global outbreak of the new crown epidemic, GHDDI launched drug research and development for the new crown 3CL protease in early 2020, starting from its enzyme function and structure, and through the cooperation of medicinal chemistry, viral biology, structural biology and data science teams, successfully designed and synthesized a series of effective compounds, of which GDI-3549 and GDI-4405 showed a high degree of druggability. In May 2021, Pfizer announced that it was advancing PF-07321332 (Nirmatrelvir) into the clinic. Given that the compound is the same structural compound as GDI-3549 independently designed and discovered by GHDDI in 2020, GHDDI selected the better compound GDI-4405 as the clinical drug candidate molecule.

3CL protease, as the main protease of the new coronavirus, is necessary for the replication and growth of the virus, so it is also an excellent antiviral drug target. Several of the antiviral (HIV, HCV) drugs on the market target 3CL protease. Among them, the inhibitors of HIV 3CL protease Lopinavir and Ritonavir have only weak inhibitory activity of the 3CL protease of the new crown virus in vitro, and have been proved ineffective in clinical tests for patients infected with the new crown virus. Therefore, specific strong inhibitors of 3CL proteases against the new crown virus are particularly important. Recently, the US FDA temporarily authorized the use of Pfizer Paxlovid, and the target of the specific drug molecule Nirmatrelvir is 3CL protease.

Currently, Pfizer Paxlovid is the world's only highly effective and approved oral small molecule drug specifically for the new crown virus. In less than two years, it was discovered from the source target to the final approval of clinical trials, which is an unprecedented miracle in the history of pharmaceuticals. "This is due to the accumulation of Pfizer's target drugs for SARS in 2003, and the incomparable investment of other institutions", Ding Sheng said, "GHDDI can independently design and discover the same compound GDI-3549 as Pfizer approved drugs, and another independently designed compound GDI-4405 is superior to Pfizer approved drugs in multiple in vitro head-to-head comparisons, demonstrating GHDDI's ability to do real source innovation from the target." By bringing together the world's top resources, giving full play to the advantages of Chinese characteristics, benefiting from the stable investment of government-private capital cooperation (PPP), and the mechanism of independent operation of R&D centers, the innovation vitality and technological transformation potential of scientific researchers have been fully released. ”