Ficolin-2 Plasma Level Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease.

Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (ρ = −0.49, p < 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0/F1 (median 4753 ng/mL) to F2−F3−F4 (2760 ng/mL) and in cirrhotic subjects (1418 ng/mL). The diagnostic performance of FCN-2 in detecting F ≥ 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate/advanced) significantly improving the fibrosis diagnostic algorithms.

Recent advances in the discovery and development of glyoxalase I inhibitors.

Glyoxalase I (GLO1) is a homodimeric Zn2+-metalloenzyme that catalyses the transformation of methylglyoxal (MG) to d-lacate through the intermediate S-d-lactoylglutathione. Growing evidence indicates that GLO1 has been identified as a potential target for the treatment cancer and other diseases. Various inhibitors of GLO1 have been discovered or developed over the past several decades including natural or natural product-based inhibitors, GSH-based inhibitors, non-GSH-based inhibitors, etc. The aim of this review is to summarize recent achievements of concerning discovery, design strategies, as well as pharmacological aspects of GLO1 inhibitors with the target of promoting their development toward clinical application.

Beyond the beaten path: improving natural products bioprospecting using an eco-evolutionary framework - the case of the octocorals.

Marine natural products (NPs) represent an impressive source of novel bioactive molecules with major biotechnological applications. Nevertheless, the usual chemical and applied perspective leading most of bioprospecting projects come along with various limitations blurring our understanding of the extensive marine chemical diversity. Here, we propose several guidelines: (i) to optimize bioprospecting and (ii) to refine our knowledge on marine chemical ecology focusing on octocorals, one of the most promising sources of marine NPs. We identified a significant phylogenetic bias in the octocoral bioprospecting, which calls for the development of a concerted discovery strategy. Given the gap existing between the number of isolated NPs and the knowledge regarding their functions, we provide an ecologically centered workflow prioritizing biological function ahead of chemical identification. Furthermore, we illustrate how -omic technologies should rapidly increase our knowledge on solving different aspects of the ecology and evolution of marine NPs.

Confronting the challenges of discovery of novel antibacterial agents.

Bacterial resistance is inevitable and is a growing concern. It can be addressed only by discovery and development of new agents. However the discovery and development of new antibacterial agents are at an all time low. This article broadly examines the historical as well as current status of antibacterial discovery and provides some perspective as how to address some of the challenges.

Discovery of cysteine-targeting covalent histone methyltransferase inhibitors.

Post-translational methylation of histone lysine or arginine residues by histone methyltransferases (HMTs) plays crucial roles in gene regulation and diverse physiological processes and is implicated in a plethora of human diseases, especially cancer. Therefore, histone methyltransferases have been increasingly recognized as potential therapeutic targets. Consequently, the discovery and development of histone methyltransferase inhibitors have been pursued with steadily increasing interest over the past decade. However, the disadvantages of limited clinical efficacy, moderate selectivity, and propensity for acquired resistance have hindered the development of HMTs inhibitors. Targeted covalent modification represents a proven strategy for kinase drug development and has gained increasing attention in HMTs drug discovery. In this review, we focus on the discovery, characterization, and biological applications of covalent inhibitors for HMTs with emphasis on advancements in the field. In addition, we identify the challenges and future directions in this fast-growing research area of drug discovery.

A target-based discovery from a parasitic helminth as a novel therapeutic approach for autoimmune diseases.

BACKGROUND: Regulatory T cells (Tregs) can alleviate the development of autoimmune and inflammatory diseases, thereby proposing their role as a new therapeutic strategy. Parasitic helminths have co-evolved with hosts to generate immunological privilege and immune tolerance through inducing Tregs. Thus, constructing a "Tregs-induction"-based discovery pipeline from parasitic helminth is a promising strategy to control autoimmune and inflammatory diseases. METHODS: The gel filtration chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC) were used to isolate immunomodulatory components from the egg extracts of Schistosoma japonicum. The extracted peptides were evaluated for their effects on Tregs suppressive functions using flow cytometry, ELISA and T cell suppression assay. Finally, we carried out colitis and psoriasis models to evaluate the function of Tregs induced by helminth-derived peptide in vivo. FINDINGS: Here, based on target-driven discovery strategy, we successfully identified a small 3 kDa peptide (SjDX5-53) from egg extracts of schistosome, which promoted both human and murine Tregs production. SjDX5-53 presented immunosuppressive function by arresting dendritic cells (DCs) at an immature state and augmenting the proportion and suppressive capacity of Tregs. In mouse models, SjDX5-53 protected mice against autoimmune-related colitis and psoriasis through inducing Tregs and inhibiting inflammatory T-helper (Th) 1 and Th17 responses. INTERPRETATION: SjDX5-53 exhibited the promising therapeutic effects in alleviating the phenotype of immune-related colitis and psoriasis. This study displayed a screening and validation pipeline of the inducer of Tregs from helminth eggs, highlighting the discovery of new biologics inspired by co-evolution of hosts and their parasites. FUNDING: This study was supported by the Natural Science Foundation of China (82272368) and Natural Science Foundation of Jiangsu Province (BK20211586).

A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identify the most highly expressed cell surface proteins. We annotate candidate protein expression in many healthy tissues and validate the expression of promising targets in 30+ patient samples with relapsed/refractory MM, as well as in primary healthy hematopoietic stem cells and T cells by flow cytometry. Six candidates (ILT3, SEMA4A, CCR1, LRRC8D, FCRL3, IL12RB1) and B cell maturation antigen (BCMA) present the most favorable profile in malignant and healthy cells. We develop a bispecific T cell engager targeting ILT3 that shows potent killing effects in vitro and decreased tumor burden and prolonged mice survival in vivo, suggesting therapeutic relevance. Our study uncovers MM-associated antigens that hold great promise for immune-based therapies of MM.

[Differential discovery strategies of therapeutic antibody drugs].

Therapeutic antibody drugs have achieved great success in clinical practice. However, their efficacy and safety still need to be improved. At the same time, excessive concentration of drug targets will cause problems such as repeated development and waste of resources. Therefore, pharmaceutical companies need to explore differentiated discovery strategies when researching antibody drugs in order to survive and develop in the fierce market competition. In this paper, the differential development strategy of therapeutic antibody drugs is discussed from the aspects of drug sources and formats, drug target selection, drug mechanism and differential drug characteristics.

The "Century of Biology" and the Evolving Role of Medicinal Chemists in Neuroscience.

Society expects that the wave of contemporary new discoveries in biological sciences will soon lead to novel treatments for human diseases, including many devastating brain disorders. Historically, medicinal chemists have contributed to drug discovery teams in ways that synergize with those from their partner sciences, and help transform new knowledge into the ultimate tangible asset: a new drug. The optimal balance of resources and the right strategy to minimize the risk of late clinical failure may differ for different therapeutic indications. Recent progress in the oncology and neuroscience therapeutic areas is compared and contrasted, in particular looking at the biological target space and functional attributes of recently FDA-approved drugs and those in the late clinical pipeline. Medicinal chemists are poised to have major influence in neuroscience drug research, and examples of areas of potential impact are presented, together with a discussion of the soft skills they bring to their project teams and why they have been so impactful.