Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects

Abstract

Macromolecular (pro)drugs hold much promise as broad-spectrum antiviral agents as either microbicides or carriers for intracellular delivery of antiviral drugs. Intriguing opportunity exists in combining the two modes of antiviral activity in the same polymer structure such that the same polymer acts as a microbicide and also serves to deliver the conjugated drug (ribavirin) into the cells. We explore this opportunity in detail and focus on the polymer backbone as a decisive constituent of such formulations. Fourteen polyanions (polycarboxylates, polyphosphates and polyphosphonates, and polysulfonates) were analyzed for blood pro/anti coagulation effects, albumin binding and albumin aggregation, inhibitory activity on polymerases, cytotoxicity, and anti-inflammatory activity in stimulated macrophages. Ribavirin containing monomers were designed to accommodate the synthesis of macromolecular prodrugs with disulfide-exchange triggered drug release. Kinetics of drug release was fast in all cases however enhanced hydrophobicity of the polymer significantly slowed release of ribavirin. Results of this study present a comprehensive view on polyanions as backbone for macromolecular prodrugs of ribavirin as broad-spectrum antiviral agents.

Per‐glycosylation of the Surface‐Accessible Lysines: One‐Pot Aqueous Route to Stabilized Proteins with Native Activity

“…For albumin, we investigated protein binding to its cognate neonatal receptor, FcRn and observed that regardless of protein glycosylation degree, binding constants remained very similar (Figure 2A). Natural capacity of albumin to bind hydrophobic substrates, which is widely used as a tool of drug delivery to extend circulation lifetime of drugs and/or to achieve lymphoid drug targeting, [34] was also unperturbed by surface glycosylation: dansyl‐labelled arginine and sarcosine exhibited quantitatively similar binding profiles to Sudlow I and II hydrophobic binding pockets of albumin, respectively, [35] irrespective of the extent of glycosylation (Figure 2B for dansyl sarcosine binding to Sudlow II site; data for Sudlow I see Supporting Information Figure S3). Albumin digestion with Proteinase K was indistinguishable between the pristine and the glycosylated albumin (Figure 2C).…”

Broad‐Spectrum Antiviral Agents Based on Multivalent Inhibitors of Viral Infectivity

“…Indeed, polyanions exhibit anticoagulant and anti‐inflammatory activity, and interact with serum albumin (causing albumin aggregation). [ 35 ] Together with the failure of polyanions as injectable inhibitors of infectivity of HIV, this signifies that systemic administration of polyanions is not a viable measure.…”

Self‐Immolative RAFT‐Polymer End Group Modification

“…[ 41 ] This approach has successfully been applied by the Zelikin group to various RAFT‐polymerizable monomers carrying different types of drugs via this self‐immolative linker strategy. [ 42–50 ]…”

“…[41] This approach has successfully been applied by the Zelikin group to various RAFT-polymerizable monomers carrying different types of drugs via this selfimmolative linker strategy. [42][43][44][45][46][47][48][49][50] Additionally, self-immolative systems have also been developed in recent years to enable the reversible attachment of polymer chains to proteins. Besides reversible PEGylation by thiolthioester exchange with self-immolation by cyclization, [51] there are also approaches that use 1,6-elimination linkers, exploiting esterases, [52] thiol-disulfide exchange, [53] or azoreductases [54] as trigger mechanisms.…”