Doxycycline interferes with zika virus serine protease and inhibits virus replication in human skin fibroblasts

• Main Authors: Chong Teoh, Teow, Al-Harbi, Sawsam J., Abdulrahman, Ammar Yasir, Rothan, Hussin A.
• Format: Article
• Published: MDPI 2021
• Subjects: QH301 Biology; R Medicine (General)
• Online Access: http://eprints.um.edu.my/26419/
• Institution: Universiti Malaya

Zika virus (ZIKV) represents a re-emerging threat to global health due to its association with congenital birth defects. ZIKV NS2B-NS3 protease is crucial for virus replication by cleaving viral polyprotein at various junctions to release viral proteins and cause cytotoxic effects in ZIKV-infected cells. This study characterized the inhibitory effects of doxycycline against ZIKV NS2B-NS3 protease and viral replication in human skin cells. The in silico data showed that doxycycline binds to the active site of ZIKV protease at a low docking energy (-7.8 Kcal/mol) via four hydrogen bonds with the protease residues TYR1130, SER1135, GLY1151, and ASP83. Doxycycline efficiently inhibited viral NS2B-NS3 protease at average human temperature (37 degrees C) and human temperature with a high fever during virus infection (40 degrees C). Interestingly, doxycycline showed a higher inhibitory effect at 40 degrees C (IC50 = 5.3 mu M) compared to 37 degrees C (9.9 mu M). The virus replication was considerably reduced by increasing the concentration of doxycycline. An approximately 50% reduction in virus replication was observed at 20 mu M of doxycycline. Treatment with 20 mu M of doxycycline reduced the cytopathic effects (CPE), and the 40 mu M of doxycycline almost eliminated the CPE of human skin cells. This study showed that doxycycline binds to the ZIKV protease and inhibits its catalytic activity at a low micro-molecular concentration range. Treatment of human skin fibroblast with doxycycline eliminated ZIKV infection and protected the cells against the cytopathic effects of the infection.