Excavating Childhood: Fairytales, Monsters and Abuse Survival in Lynda Barry’s What It Is

This article investigates the excavation of abused childhood in Lynda Barry’s What It Is. Looking at the centrality of childish play, fairy tales and the Gorgon in the protagonist’s effort to cope with maternal abuse, it argues that comics complicate the life narrative and allow the feminist reconfiguration of the monstrous mother of Western psychoanalysis and art

Novel Inhibitor Binding Site Discovery on HIV‑1 Capsid N‑Terminal Domain by NMR and X‑ray Crystallography

The HIV-1 capsid (CA) protein, a domain of Gag, which participates in formation of both the mature and immature capsid, represents a potential target for anti-viral drug development. Characterization of hits obtained via high-throughput screening of an <i>in vitro</i> capsid assembly assay led to multiple compounds having this potential. We previously presented the characterization of two inhibitor series that bind the N-terminal domain of the capsid (CA_NTD), at a site located at the bottom of its helical bundle, often referred to as the CAP-1 binding site. In this work we characterize a novel series of benzimidazole hits. Initial optimization of this series led to compounds with improved <i>in vitro</i> assembly and anti-viral activity. Using NMR spectroscopy we found that this series binds to a unique site on CA_NTD, located at the apex of the helical bundle, well removed from previously characterized binding sites for CA inhibitors. 2D ¹H–¹⁵N HSQC and ¹⁹F NMR showed that binding of the benzimidazoles to this distinct site does not affect the binding of either cyclophilin A (CypA) to the CypA-binding loop or a benzodiazepine-based CA assembly inhibitor to the CAP-1 site. Unfortunately, while compounds of this series achieved promising <i>in vitro</i> assembly and anti-viral effects, they also were found to be quite sensitive to a number of naturally occurring CA_NTD polymorphisms observed among clinical isolates. Despite the negative impact of this finding for drug development, the discovery of multiple inhibitor binding sites on CA_NTD shows that capsid assembly is much more complex than previously realized