Publication
The herpes simplex virus (HSV) is associated with serious conditions, such as encephalitis and blindness, and its infection is closely linked to significant vascular complications and coagulation issues, particularly in individuals with compromised immune systems. Current antiviral treatments often fall short of effectively eliminating viral shedding and face resistance and are not entirely effective in managing coagulation. HSV recognition of heparan sulfate on cell walls for entry is well-established. A possible strategy to effectively address HSV infections involves developing agents with both antiviral and anticoagulant properties. Recently, multivalent entry inhibitors (MEI) against HSV have been developed. Among the most promising candidates is an MEI that uses a beta-cyclodextrin as a scaffold to hold six elongated 11-methylene long alkyl (C11) chains, each terminated with sodium sulfonates. This MEI exhibits irreversible inhibition of viral infectivity (virucidal mechanism) with some good results in vivo. The role of the cyclodextrin core is simply to hold the arms together. Here, we present an investigation of other potential core candidates, and we compare their structure-activity for viral inhibition. We find that all cores functionalized with C12 chains terminated with either sulfate or sulfonate are effective in inhibiting both HSV1 and HSV2, all with a virucidal mechanism. We find significant differences in the half inhibitory concentration (IC50), the best core being p-tert-butylcalix[4]arene when functionalized with C12 sodium sulfonate terminated arms. This core showed an IC50 of 8.3 mu M against HSV-1 and 10.6 mu M against HSV-2 a drastic improvement over the beta-cyclodextrin. We investigated the anticoagulant property of our lead compound by inhibiting factor Xa, a key enzyme in coagulation cascade pathways, and found similar inhibition to that of the FDA-approved drug fondaparinux. Thus, our compound presents a nonsaccharide-based prophylactic dual inhibitor against HSV infections.