ABSTRACT
Many clinically important viruses, including influenza A, SARS-CoV-1, adenoviruses, and DNA tumour viruses such as Kaposi’s sarcoma herpesvirus use multivalent binding to sialic acid (SA) to infect cells, or to modulate immune responses through interactions with sialylated attachment factors that facilitate virus infectivity and/or host survival. Molecular scaffolds rich in SA that bind virions with high avidity may therefore be useful as anti-infective medicines. We generated a panel of 12 of these molecules using fragment-crystallisable scaffolds in CHO-S cells that are rich in SA. The viral surface protein of influenza A virus (IAV), haemagglutinin, binds SA for cell entry, and so we tested the activity of these compounds against this virus. Two of the sialylated Fc-molecules reduced IAV haemagglutination activity by up to 64-fold. However, the same molecules enhanced virus infectivity of A549 cultured cells. To explain the increased viral titres, we postulated that sialylated Fcs may be anti-inflammatory. However, sialylated Fc multimers were instead pro-inflammatory; they induced chemokine/cytokine responses from differentiated human THP-1 derived macrophages, including raised IL-8 and MIP-1α/β, that mimicked responses driven by universal type I interferon. Steric targeting of SA to block virus entry may therefore have unexpected effects in target cells that currently preclude their use for medical intervention.