Recent advances in developing small-molecule inhibitors against SARS-CoV-2.

The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.

Hypervalent Iodine(III)-Promoted C3-H Regioselective Halogenation of 4-Quinolones under Mild Conditions.

A simple and practical protocol for the C3-H regioselective halogenation of 4-quinolones by the action of potassium halide salt and PIFA/PIDA in good to excellent yields was developed. The current approach provides feasible access to the diversity of C3-halgenated 4-quinolones at room temperature with high regioselectivity and good functional group tolerance, from which bioactive compounds can be easily constructed. Moreover, the current method featured eco-friendly, operational convenience and is suitable for halogenation in a gram scale of 4-quinolones in water without sacrificing yields.

Description of a new species, Sillago nigrofasciata sp. nov. (Perciformes, Sillaginidae) from the southern coast of China.

A new Sillago species, the black-banded sillago, Sillago nigrofasciata sp. nov., is described based on 302 specimens sampled from the southern coast of China. Morphological comparisons have been conducted between the new species and ten other Sillago species. The results show that the new species is characterized by a black mid-lateral band below the lateral line when fresh; other characteristics are similar to those of Sillago sihama but subtle differences exist on the swim bladder between Sillago nigrofasciata sp. nov. and S. sihama. A detailed description and illustrations are provided for the new species. The validity of this new species is also supported by a genetic comparison using sequences of the mitochondrial cytochrome c oxidase subunit I (COI) gene.

Receptor-binding domain-specific human neutralizing monoclonal antibodies against SARS-CoV and SARS-CoV-2.

The outbreaks of severe acute respiratory syndrome (SARS) and Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV and SARS-CoV-2, respectively, have posed severe threats to global public health and the economy. Treatment and prevention of these viral diseases call for the research and development of human neutralizing monoclonal antibodies (NMAbs). Scientists have screened neutralizing antibodies using the virus receptor-binding domain (RBD) as an antigen, indicating that RBD contains multiple conformational neutralizing epitopes, which are the main structural domains for inducing neutralizing antibodies and T-cell immune responses. This review summarizes the structure and function of RBD and RBD-specific NMAbs against SARS-CoV and SARS-CoV-2 currently under development.

Influenza virus glycoprotein-reactive human monoclonal antibodies.

Influenza continues to be a significant public health challenge. Two glycoproteins on the surface of influenza virus, hemagglutinin and neuraminidase, play a prominent role in the process of influenza virus infection and release. Monoclonal antibodies targeting glycoproteins can effectively prevent the spread of the virus. In this review, we summarized currently reported human monoclonal antibodies targeting glycoproteins of influenza A and B viruses.

Development of small-molecule inhibitors against hantaviruses.

Hantavirus (HV), a pathogen of animal infectious diseases that poses a threat to humans, has attracted extensive attention. Clinically, HV can cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), between which HFRS is mostly in Eurasia, and HPS is mostly in the Americas. This paper reviews the research progress of small-molecule inhibitors of HV.

Farnesyl Pyrophosphate Synthase as a Target for Drug Development: Discovery of Natural-Product-Derived Inhibitors and Their Activity in Pancreatic Cancer Cells.

Human farnesyl pyrophosphate synthase (Homo sapiens FPPS, HsFPPS) is a target for treating bone resorption diseases and some cancers. HsFPPS is potently inhibited by bisphosphonates, but due to poor cell penetration and distribution in soft tissue, there is currently interest in the development of non-bisphosphonate inhibitors as cancer therapeutics. Here, we report the discovery and development of HsFPPS inhibitors based on the phenolic diterpene carnosic acid (CA), an antimicrobial found in rosemary and sage, which showed better cellular anticancer activities than the bisphosphonate drug zoledronate in pancreatic cancer cell lines, as well as an HsFPPS-dependent mechanism of action. Hit-to-lead optimization of CA improved HsFPPS inhibition by >100-fold. A slow dissociation inhibition pattern and a noncompetitive allosteric binding mode were found, and cellular mechanism-of-action studies showed that these inhibitors inhibit tumor cell growth primarily by inhibiting HsFPPS, leading to downregulation of Ras prenylation and cell apoptosis. The discovery of this series of compounds together with proof-of-mechanism in pancreatic cancer cells may pave the way for targeting HsFPPS in soft tissue cancers using natural-product-derived inhibitors.

The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery.

Motivated by the clinical observation that interruption of the mevalonate pathway stimulates immune responses, we hypothesized that this pathway may function as a druggable target for vaccine adjuvant discovery. We found that lipophilic statin drugs and rationally designed bisphosphonates that target three distinct enzymes in the mevalonate pathway have potent adjuvant activities in mice and cynomolgus monkeys. These inhibitors function independently of conventional "danger sensing." Instead, they inhibit the geranylgeranylation of small GTPases, including Rab5 in antigen-presenting cells, resulting in arrested endosomal maturation, prolonged antigen retention, enhanced antigen presentation, and T cell activation. Additionally, inhibiting the mevalonate pathway enhances antigen-specific anti-tumor immunity, inducing both Th1 and cytolytic T cell responses. As demonstrated in multiple mouse cancer models, the mevalonate pathway inhibitors are robust for cancer vaccinations and synergize with anti-PD-1 antibodies. Our research thus defines the mevalonate pathway as a druggable target for vaccine adjuvants and cancer immunotherapies.

The Crystal Structure of a Class of Cyclases that Catalyze the Cope Rearrangement.

Found recently in stignomatales, the Stig cyclases catalyze the Cope rearrangement and intramolecular cyclization to produce complex indole alkaloids. Five crystal structures were solved of subfamily 1 and 2 Stig cyclases, which adopt a ß-sandwich fold like the non-catalytic carbohydrate-binding motif. Several complex structures were also determined of indole-based compounds, which are bound to the hydrophobic terminal cavity, where a conserved Asp residue makes an H-bond to the indole N and triggers the acid-catalyzed Cope rearrangement. Through analyzing the enzyme-ligand interactions and mutagenesis experiments, several aromatic residues were found important in catalysis. Apart from a common substrate binding mode and catalytic mechanism, potential subfamily variations that may attribute to the different product specificity are implicated. These results shall expand our scope of enzymology, in particular for further investigation of the biosynthetic Cope rearrangement.

The taxonomic status and sister group relationship of the cardinalfish species Jaydia striatodes (Percomorphaceae: Apogonidae).

Two similar cardinalfish species, Jaydia striatodes and J. striata, were compared morphologically and genetically, using the fragment of cytochrome oxidase subunit I (COI) gene of the mitochondrial DNA. The results confirmed the validity of both species and their sister group relationship. The species formed well-supported monophyletic clades that were distinctly separate with mean sequence divergence of 12.2%. Jaydia striatodes is distinct in having 4-5 + 12-13 gill rakers; 3 + 11-12 developed gill rakers; 9 gill rakers on the first ceratobranchial; 3-9 weak serration at the angle of preopercular edge; and a usually blackish distal half of anal fin. Jaydia striatodes was recorded for the first time from Beibu Gulf, China, and from Vietnam.