Use of 6'-Fluoro-Neplanocin A Derivatives Against Chikungunya Virus
Chikungunya virus (CHIKV) is an emerging human pathogen that is transmitted by mosquitoes and often causes very severe, debilitating and persisting joint pains, which can last for many months. Since 2006, the virus has re-emerged in an epidemic form and its geographical distribution has rapidly expanded, from Africa to large parts of Asia and South- and Central America. Local outbreaks have also been reported from France and Italy over the past years, due to the presence of the tiger mosquito. Over 6 million people have been affected by CHIKV since its re-emergence in 2006. There are currently no registered vaccines or antiviral drugs available to prevent or treat CHIKV infections.
Researchers at Leiden University Medical Center have identified 6’-Fluoro-Neplanocin derivatives and related molecules as inhibitors of CHIKV replication in cell culture at submicromolar concentrations (EC50 ~0.2 uM) without apparent cytotoxicity, resulting in a selectivity index of >1000.
Selection of resistant variants and reverse genetics studies demonstrated that CHIKV protein nsP1 is the target of the compound (requiring 2 mutations for resistance). nsP1 is the methyltransferase/guanylyltransferase that is involved in capping of the viral RNA. Biochemical studies confirmed that nsP1 is the target of our compounds. The compounds appear to have a dual mode of action: directly targeting the viral protein nsP1 and inhibiting host SAH hydrolase, causing an indirect inhibition of the unique viral RNA methylation mechanism. The molecules are interesting candidates that might be advanced further into clinical development for the treatment of CHIKV infections.
Stage of Development:
Collaborative project between Seoul National University (Medicinal Chemistry, prof. Lak Shin Jeong) and Leiden University Medical Center (Virology, dr. M.J. van Hemert). The compounds will now undergo ADMEtox analysis and determination of anti-CHIKV efficacy in a CHIKV mouse infection model.
Development of antiviral drugs for therapeutic use (patients suffering from the persistent CHIKV arthritis) or prophylactic use (in outbreak settings or for travellers to the many tropical and subtropical areas where CHIKV is now endemic).
Luris reference numberS190405-5992-18318
Data available on request
Seeking development partner.