A Nearly 20-Year Journey to Success of Azvudine for Antiviral Therapy

Abstract

Modified nucleosides, particularly those with 4'-modifications, are significant nucleosides used in antiviral treatments. The drug discovery campaign of Azvudine starts from 2′-deoxynucleoside, followed by extensive modifications, such as introducing the 4’-position substitutions, a 2’-β-fluoro atom, and changing the nucleobases. Azvudine acts potently toward various HIV-1 strains by inhibiting HIV-1 reverse transcription and preventing Vif-induced A3G degradation, representing the first-in-class dual-acting antiviral agent. In July 2021, the NMPA conditionally approved Azvudine as an adjunct therapy for adult patients with high levels of HIV-1 virus load when combined with NRTIs or NNRTIs. Azvudine is capable of inhibiting SARS-CoV-2, as well as its variants, including Alpha, Beta, Delta, and Omicron. Clinical trials have revealed its real-world effectiveness among hospitalized severely or critically ill COVID-19 patients or those with pre-existing conditions. On July 25th, 2022, the NMPA granted conditional authorization approving Azvudine as China's first domestic oral anti-COVID-19 agent. Generally, Azvudine at therapeutic doses is safe and well-tolerated in clinical settings. Azvudine got approval from the National Health Commission and National Administration of Traditional Chinese Medicine on August 9th to be used in the "Diagnosis and Treatment Program for Novel Coronavirus Pneumonia (Ninth Edition)" for treating common COVID-19 adult patients. On August 12th, 2022, it was also approved by the National Healthcare Security Administration to be added to the list of medical reimbursements. Of note, the achievements related to Azvudine were indexed in the China Basic Research Development Report in Thirty-Five of 2022. Azvudine was also approved on January 5th, 2023, to be used in the "Diagnosis and Treatment Program for Novel Coronavirus Pneumonia (Tenth Edition)" for treating COVID-19 patients. In February 2023, the Ministry of Health of the Russian Federation approved the usage of Azvudine among individuals infected with SARS-CoV-2.

What is the most favorite and original chemistry developed in your research group?

My favorite chemistries are always those that enable efficient access to drug molecules.

How do you get into this specific field? Could you please share some experiences with our readers?

The virus uses nucleosides as raw materials for replication. Learned from this biological process, I have been devoted to, for decades, synthesizing nucleoside mimics. Once attached to the 3'-hydroxy group of the virus RNA chain, these nucleoside analogs can effectively inhibit virus replication. Hard work pays off! We have developed a series of novel 4’-modified nucleosides, among which Azvudine has been officially approved for treating HIV in China and COVID-19 in both China and Russia. Notably, Azvudine is the first Chinese oral anti-COVID-19 agent. The experiences I would like to share with the readers are many, but emphases are placed on thinking critically and working enthusiastically.

How do you supervise your students?

I generally supervise students differently according to their aptitudes. For those keen on scientific work, I always suggest them learn from the literature, and practice makes perfect, think critically, and work with passion.

What is the most important personality for scientific research?

The personalities such as curiosity, creativity, persistence, and the ability to think critically and solve problems matter most for scientific research. Furthermore, what sets successful scientists apart is their passion for their work and their ability to persevere in facing challenges and setbacks.

Who influences you mostly in your life?

My Ph.D. supervisor profoundly fuels my passion for academia and, to some extent, reshapes my personality.