Cooperative Orthogonal Macromolecular Assemblies with Broad Spectrum Antiviral Activity, High Selectivity, and Resistance Mitigation

• DOI: 10.1021/acs.macromol.6b00091
• Publication Date: 2016-03-17T18:49:55Z
• Authors: Koji Ichiyama; Chuan Yang; Lakshmi Chandrase...; Shaoqiong Liu; Lijun Rong; Yue Zhao; Shujun Gao; Ashlynn Lee; Kenji Ohba; Youichi Suzuki; Yoshiyuki Yoshinaka; Kunitada Shimotohno; Kei Miyakawa; Akihide Ryo; James Hedrick; Naoki Yamamoto; Yi Yan Yang
• Keywords: Sindbis virus

Treatment of viral infections continues to be elusive owing the variance in virus structure (RNA, DNA, and enveloped nonenveloped viruses) together with their ability rapidly mutate garner resistance. Here we report a general strategy prevent infection using multifunctional macromolecules that were designed have mannose moieties compete viruses for immune cells, basic amine groups block entry through electrostatic interactions replication by neutralizing endosomal pH. We showed cells treated antiviral polymers inhibited TIM receptors from trafficking virus, likely hydrogen-bonding interactions, EC50 values ranging 2.6 6.8 mg/L, depending on type receptors. Molecular docking computations revealed an unexpected, general, specific surface proteins, cell binding assay demonstrated significant reduction after incubating or polymers. Moreover, mannose-functionalized effectively prevented infecting cells. Representative each category including dengue, influenza, Chikungunya, Enterovirus 71, Ebola, Marburg, herpes simplex surveyed, was at polymer concentrations as low 0.2 mg/L very high selectivity (>5000) over mammalian The generality these cooperative orthogonal (electrostatic hydrogen-bonding) provides broad-spectrum activity. As mechanism is based nonspecific supramolecular between amino acid residues mannose/cationic macromolecule, form virus–polymer polymer−cell assemblies can occur regardless mutation, preventing drug resistance development.