Adélie Gothland

Human Herpesvirus 8 (HHV-8) is associated with three main severe orphan malignancies, Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD), and primary effusion lymphoma (PEL), which present few therapeutic options. We identified the antimalarial primaquine diphosphate (PQ) as a promising therapeutic candidate for HHV-8-associated PEL and KS. Indeed, PQ strongly reduced cell viability through caspase-dependent apoptosis, specifically in HHV-8-infected PEL cells. Reactive oxygen species (ROS)- and endoplasmic reticulum (ER) stress-mediated apoptosis signaling pathways were found to be part of the in vitro cytotoxic effect of PQ. Moreover, PQ treatment had a clinically positive effect in a nonobese diabetic (NOD)/SCID xenograft PEL mouse model, showing a reduction in tumor growth and an improvement in survival. Finally, an exploratory proof-of-concept clinical trial in four patients harboring severe KS was conducted, with the main objectives to assess the efficacy, the safety, and the tolerability of PQ, and which demonstrated a positive efficacy on Kaposi’s sarcoma-related lesions and lymphedema.

To imitate Nature's ability to form cooperative self‐assemblies using entirely artificial molecular tools and to confer them with properties is still a true challenge. Here we show that cyclodextrins bridged with an ammonium linker which bears a hydrophobic substituent efficiently form supramolecular polymers at millimolar concentrations, avoiding the competing self‐inclusion and head‐to‐head processes. Notably, such assembly can occur at micromolecular concentrations in the presence of genomic DNA, resulting in efficient DNA compaction that is reversible upon addition of a competitive guest, and demonstrating their highly cooperative interaction. We finally show that the supramolecular polymer also cooperatively interacts with siRNA and allows its transfection.