Here we report the first systematic study of BCPs in S. mansoni. Using a combination of sequence similarity and domain-based searches, applied previously to the characterisation of schistosome histone methyltransferases (HMTs) and histone demethylases (HDMs), we have identified 22 BCPs in S. mansoni containing 29 distinct BRDs. We have focused our investigation on SmBRD3 (Smp_147950), due to its relatively high temporal expression when compared to most other SmBCPs, and similarity to the human bromodomain and extra terminal domain (BET) family of BCPs. SmBRD3 shares 37.5% sequence identity with human BRD3 (HsBRD3) and similar to the BET BCPs, possesses two BRDs, SmBRD3 (1) and SmBRD3 (2). Using differential scanning fluorimetry (DSC) and isothermal titration calorimetry (ITC) we identified a number of human bromodomain ligands that bind to either SmBRD3 (1) or SmBRD3 (2). An X-ray crystal structure of I-BET726 bound to SmBRD3(2) allowed the structure-based optimisation of this compound series to give the quinoline-derived compound 15, which has a Kd value of 364 ± 26.3 nM for SmBRD3 (2). In a variety of whole organism phenotypic assays, the ethyl ester prodrug of compound 15, compound 22, demonstrated profound effects on both larval schistosomula and sexually reproductive adult worms. Interestingly, compound 22 also prevents the developmental transformation of snailinfective miracidia into asexually proliferative sporocysts. This suggests a role for SmBRD3 in the parasite developmental life cycle, mirroring the role of the BET bromodomains in humans. Our use of a structure-and target-based approach has enabled the rapid development of high affinity ligands for SmBRD3. While further work is required to determine the selectivity of the compounds, the development of chemical tools with defined cellular targets paves the way for contemporary medicinal chemistry techniques to be applied to S. mansoni. Where no family can be defined, the BCP is labelled 'currently unclassified'. Gene ID (Smp; according to the S. mansoni v7 genome annotation; IDs remain stable in the v10 assembly), common name (in parentheses) and total protein length (in number of amino acids -aa) are all While BRDs have previously been identified in the S. mansoni histone acetyltransferases (HATs) SmGCN5 17 , SmCBP1 and SmCBP2 , there has been no systematic search for these protein modules in the parasite proteome more generally. Additionally, while there have been some studies in which human BRD ligands have been assessed for their phenotypic effects on S. mansoni, there has not been a rational design approach taken to identifying and optimising ligands for S. mansoni BRDs. Using a combination of genome-and domain-based bioinformatic searches of the S. mansoni genome, we identified 29 putative BRDs found in 22 distinct BCPs (Figure ). This differentially expressed gene family (Figure ) includes the previously characterised SmGCN5 17 , SmCBP1 and SmCBP2 proteins , but also a number of previously uncharacterised BCPs. One BCP, that is highly expressed throughout the S. mansoni lifecycle, possesses 37.5% sequence identity to human BRD3 (HsBRD3) and 33.2% identity to human BRD4 (HsBRD4); we have annotated this BCP as S. mansoni bromodomain-containing protein 3 (SmBRD3; Smp_147950; UniProt: G4V8V7), in analogy to HsBRD3. Sequence analysis shows that, similar to its human homolog, SmBRD3 possesses two bromodomains [SmBRD3(1) and SmBRD3 (2)] that are located towards the N-terminus of the protein (Figure ), and which are separated by approximately 100 residues (Figure ). respectively. The region identified as the first bromodomain is indicated with a green bar and the region identified as the second bromodomain is indicated with a white bar. Sequences were aligned using MUSCLE and the resulting multiple sequence alignment was visualised using ESPript 3 server. Extensive structural studies on the human BET BCPs (including HsBRD3) have identified the residues that are important for its interactions with acetylated lysine (KAc) residues in target proteins. In HsBRD4 (1), these are Y97 and N140; N140 forms a hydrogen bond directly with KAc, while Y97 interacts with KAc through a water-mediated hydrogen bond. The primary sequence of SmBRD (1) and SmBRD3 (2) indicates that both of these BRDs possess equivalent residues to Y97 and N140, [Y67 & N110 in SmBRD3(1) and Y296 & N339 in SmBRD3(2)], indicating that they are canonical BRDs and that they can bind to KAc. A second region of the BET BRDs that is important for binding to KAc, and small molecule ligands, is the WFP shelf. Named after the residues that define it, this region binds to the lipophilic chain of a second KAc residue when bound to chromatin (e.g. PDB code: 3UVX). The lipophilic nature of this region has been exploited in the design of BRD4 ligands, with many high affinity compounds interacting with the WPF shelf.