Rothan Hussin A, Bahrani Hirbod, Mohamed Zulqarnain, Teoh Teow Chong, Shankar Esaki M, Rahman Noorsaadah A, Yusof Rohana
Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Institute of biological sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
PLoS One. 2015 May 13;10(5):e0126360. doi: 10.1371/journal.pone.0126360. eCollection 2015.
Lack of vaccine and effective antiviral drugs against chikungunya virus (CHIKV) outbreaks have led to significant impact on health care in the developing world. Here, we evaluated the antiviral effects of tetracycline (TETRA) derivatives and other common antiviral agents against CHIKV. Our results showed that within the TETRA derivatives group, Doxycycline (DOXY) exhibited the highest inhibitory effect against CHIKV replication in Vero cells. On the other hand, in the antiviral group Ribavirin (RIBA) showed higher inhibitory effects against CHIKV replication compared to Aciclovir (ACIC). Interestingly, RIBA inhibitory effects were also higher than all but DOXY within the TETRA derivatives group. Docking studies of DOXY to viral cysteine protease and E2 envelope protein showed non-competitive interaction with docking energy of -6.6±0.1 and -6.4±0.1 kcal/mol respectively. The 50% effective concentration (EC50) of DOXY and RIBA was determined to be 10.95±2.12 μM and 15.51±1.62 μM respectively, while DOXY+RIBA (1:1 combination) showed an EC50 of 4.52±1.42 μM. When compared, DOXY showed higher inhibition of viral infectivity and entry than RIBA. In contrast however, RIBA showed higher inhibition against viral replication in target cells compared to DOXY. Assays using mice as animal models revealed that DOXY+RIBA effectively inhibited CHIKV replication and attenuated its infectivity in vivo. Further experimental and clinical studies are warranted to investigate their potential application for clinical intervention of CHIKV disease.
缺乏针对基孔肯雅病毒（CHIKV）爆发的疫苗和有效的抗病毒药物，已对发展中世界的医疗保健造成重大影响。在此，我们评估了四环素（TETRA）衍生物和其他常见抗病毒药物对CHIKV的抗病毒作用。我们的结果表明，在TETRA衍生物组中，强力霉素（DOXY）对Vero细胞中CHIKV复制的抑制作用最高。另一方面，在抗病毒药物组中，利巴韦林（RIBA）对CHIKV复制的抑制作用高于阿昔洛韦（ACIC）。有趣的是，RIBA的抑制作用也高于TETRA衍生物组中除DOXY之外的所有药物。DOXY与病毒半胱氨酸蛋白酶和E2包膜蛋白的对接研究表明，其分别与对接能量为-6.6±0.1和-6.4±0.1 kcal/mol的非竞争性相互作用。DOXY和RIBA的50%有效浓度（EC50）分别确定为10.95±2.12 μM和15.51±1.62 μM，而DOXY+RIBA（1:1组合）的EC50为4.52±1.42 μM。相比之下，DOXY对病毒感染性和进入的抑制作用高于RIBA。然而，与之相反的是，RIBA对靶细胞中病毒复制的抑制作用高于DOXY。以小鼠为动物模型的试验表明，DOXY+RIBA可有效抑制CHIKV在体内的复制并减弱其感染性。有必要进行进一步的实验和临床研究，以探讨它们在CHIKV疾病临床干预中的潜在应用。
