Viral pathogens continue to constitute a heavy burden on healthcare and socioeconomic systems. Efforts to create antiviral drugs repeatedly lag behind the advent of pathogens and growing understanding is that broad-spectrum antiviral agents will make strongest impact in future antiviral efforts. This work performs selection of synthetic polymers as novel broadly active agents and demonstrates activity of these polymers against Zika, Ebola, Lassa, Lyssa, Rabies, Marburg, Ebola, influenza, herpes simplex, and human immunodeficiency viruses. Results presented herein offer structure-activity relationships for these pathogens in terms of their susceptibility to inhibition by polymers, and for polymers in terms of their anionic charge and hydrophobicity that make up broad-spectrum antiviral agents. The identified leads cannot be predicted based on prior data on polymer-based antivirals and represent promising candidates for further development as preventive microbicides.

Uncontrolled systemic inflammatory immune triggering has hampered the clinical translation of several classes of small‐molecule immunomodulators, such as imidazoquinoline TLR7/8 agonists for vaccine design and cancer immunotherapy. By taking advantage of the inherent serum‐protein‐binding property of lipid motifs and their tendency to accumulate in lymphoid tissue, we designed amphiphilic lipid–polymer conjugates that suppress systemic inflammation but provoke potent lymph‐node immune activation. This work provides a rational basis for the design of lipid–polymer amphiphiles for optimized lymphoid targeting.

The ultimate goal of controlled, intracellulardrug delivery is to get the drug to the target cell without spilling the contents in transit and then release the entire payload upon cell entry. One of the most powerful platforms to achieve this relies on the intracellular disulfide reshuffling as a trigger for drug release form the engineered prodrugs. However, utility of disulfide reshuffling for drug release is naturally applicable only to the thiol containing molecules-ultimately leaving nearly all commercialized drugs beyond the scope of this platform. This is a drastic limitation. A cunning new tool of organic chemistry is fast entering the mainstream of prodrug design: the self-immolative linkers. This platform allows overcoming the natural chemical barrier and makes it possible to link virtually any drug to its carrier via a disulfide bond and engineer a specific intracellular release. It is a game-changing accomplishment of modern organic chemistry. The scope and limitations of this novel opportunity for medicinal chemistry and nanomedicine are outlined.

Identification and directed development of non-organic catalysts with apparent pan-enzymatic mimicry into nanozymes for efficient prodrug conversion

Ebola (EBOV) and Zika viruses (ZIKV) are responsible for recent global health threats. As no preventive vaccines or antiviral drugs against these two re-emerging pathogens are available, we evaluated whether the molecular tweezer CLR01 may inhibit EBOV and ZIKV infection. This small molecule has previously been shown to inactivate HIV-1 and herpes viruses through a selective interaction with lipid-raft-rich regions in the viral envelope, which results in membrane disruption and loss of infectivity. We found that CLR01 indeed blocked infection of EBOV and ZIKV in a dose-dependent manner. The tweezer inhibited infection of epidemic ZIKV strains in cells derived from the anogenital tract and the central nervous system, and remained antivirally active in the presence of semen, saliva, urine and cerebrospinal fluid. Our findings show that CLR01 is a broad-spectrum inhibitor of enveloped viruses with prospects as a preventative microbicide or antiviral agent.