Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen PI, Ianevski A, Lysvand H, et al. Discovery and development of safe-in-man broad-spectrum antiviral agents. Int J Infect Dis. 2020. https://doi.org/10.1016/j.ijid.2020.02.018

Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of general population from emerging and re-emerging viral diseases reinforcing the arsenal of available antiviral options. Here, we reviewed discovery and development of BSAAs and summarized the information on 119 safe-in-man agents in freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.

Colorimetric Band-aids for Point-of-Care Sensing and Treating Bacterial Infection

Sun Y, Zhao C, Niu J, Ren J, Qu X. Colorimetric band-aids for point-of-care sensing and treating bacterial infection. ACS Cent Sci. 2020. https://doi.org/10.1021/acscentsci.9b01104.

Sensing bacterial infections and monitoring drug resistance are very important for the selection of treatment options. However, the common methods of sensing resistance are limited by time-consuming, the requirement for professional personnel, and expensive instruments. Moreover, the abuse of antibiotics causes the accelerated process of bacterial resistance. Herein, we construct a portable paper-based band-aid (PBA) which implements a selective antibacterial strategy after sensing of drug resistance. The colors of PBA indicate bacterial infection (yellow) and drug resistance (red), just like a bacterial resistance colorimetric card. On the basis of color, antibiotic-based chemotherapy and Zr-MOF PCN-224-based photodynamic therapy (PDT) are used on site to treat sensitive and resistant strains, respectively. Eventually, it takes 4 h to sense, and the limit of detection is 10⁴ CFU/mL for drug-resistant E. coli. Compared with traditional PDT-based antibacterial strategies, our design can alleviate off-target side effects, maximize therapeutic efficacy, and track the drug resistance in real time with the naked eye. This work develops a new way for the rational use of antibiotics. Given the low cost and easy operation of this point-of-care device, it can be developed for practical applications.

A neurotoxin that specifically targets Anopheles mosquitoes

Contreras E, Masuyer G, Qureshi N, et al. A neurotoxin that specifically targets anopheles mosquitoes. Nature Communications. 2019;10(1):2869. https://doi.org/10.1038/s41467-019-10732-w.

Clostridial neurotoxins, including tetanus and botulinum neurotoxins, generally target vertebrates. We show here that this family of toxins has a much broader host spectrum, by identifying PMP1, a clostridial-like neurotoxin that selectively targets anopheline mosquitoes. Isolation of PMP1 from Paraclostridium bifermentans strains collected in anopheline endemic areas on two continents indicates it is widely distributed. The toxin likely evolved from an ancestral form that targets the nervous system of similar organisms, using a common mechanism that disrupts SNARE-mediated exocytosis. It cleaves the mosquito syntaxin and employs a unique receptor recognition strategy. Our research has an important impact on the study of the evolution of clostridial neurotoxins and provides the basis for the use of P. bifermentans strains and PMP1 as innovative, environmentally friendly approaches to reduce malaria through anopheline control.

Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies

Kosik I, Angeletti D, Gibbs JS, et al. Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies. J Exp Med. 2019. dx.doi.org/10.1084/jem.20181624.

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza-infected mice, likely due at least in part to NA-mediated inhibition of FcγR-dependent activation of innate immune cells by Ab bound to virions. Food and Drug Administration–approved NA inhibitors enhance anti-stem–based Fc-dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.