Newest perspectives of glycopeptide antibiotics: biosynthetic cascades, novel derivatives, and new appealing antimicrobial applications.

Glycopeptide antibiotics (GPAs) are a family of non-ribosomal peptide natural products with polypeptide skeleton characteristics, which are considered the last resort for treating severe infections caused by multidrug-resistant Gram-positive pathogens. Over the past few years, an increasing prevalence of Gram-positive resistant strain "superbugs" has emerged. Therefore, more efforts are needed to study and modify the GPAs to overcome the challenge of superbugs. In this mini-review, we provide an overview of the complex biosynthetic gene clusters (BGCs), the ingenious crosslinking and tailoring modifications, the new GPA derivatives, the discoveries of new natural GPAs, and the new applications of GPAs in antivirus and anti-Gram-negative bacteria. With the development and interdisciplinary integration of synthetic biology, next-generation sequencing (NGS), and artificial intelligence (AI), more GPAs with new chemical structures and action mechanisms will constantly be emerging.

Chemoenzymatic Synthesis of SARS-CoV-2 Homogeneous O-Linked Glycopeptides for Exploring Their Inhibition Functions.

Harnessing highly conserved peptides derived from the receptor binding domain (RBD) of spike (S) protein to construct peptide-based inhibitors is one of the most effective strategies to fight against the ever-mutating coronavirus SARS-CoV-2. But how the O-glycosylation affects their inhibition abilities has not been intensively explored. Herein, an intrinsic O-glycosylated peptide P320-334 derived from RBD was screened and homogeneous O-linked glycopeptides containing Tn (GalNAcα1-O-Ser/Thr), T (Galß1-3GalNAcα1-O-Ser/Thr), sialyl-Tn (sTn, Siaα2-6GalNAcα1-O-Ser/Thr), and sialyl-T (sT, Siaα2-3Galß1-3GalNAcα1-O-Ser/Thr) structures were first synthesized via chemoenzymatic strategies. Compared with the unglycosylated peptide, the binding of sT-P320-334 to hACE2 was enhanced to 133% and the inhibition capacity against RBD-hACE2 binding of sTn- and sT-P320-334 was significantly increased up to 150-410%. Thus, our results suggest the sialic acid residue on the terminal of short O-glycan structures might strengthen the inhibition capacities of these peptide-based inhibitors, which might provide novel optimization directions for the inhibitor design.

Glycophosphopeptical AM3 Food Supplement: A Potential Adjuvant in the Treatment and Vaccination of SARS-CoV-2.

The world is currently experiencing the coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome-2 (SARS-CoV-2). Its global spread has resulted in millions of confirmed infections and deaths. While the global pandemic continues to grow, the availability of drugs to treat COVID-19 infections remains limited to supportive treatments. Moreover, the current speed of vaccination campaigns in many countries has been slow. Natural substrates with biological immunomodulatory activity, such as glucans, may represent an adjuvant therapeutic agent to treat SARS-CoV-2. AM3, a natural glycophosphopeptical, has previously been shown to effectively slow, with no side effects, the progression of infectious respiratory diseases by regulating effects on innate and adaptive immunity in experimental models. No clinical studies, however, exist on the use of AM3 in SARS-CoV-2 infected patients. This review aims to summarize the beneficial effects of AM3 on respiratory diseases, the inflammatory response, modulation of immune response, and attenuation of muscle. It will also discuss its potential effects as an immune system adjuvant for the treatment of COVID-19 infections and adjuvant for SARS-CoV-2 vaccination.

The lysosome: A potential juncture between SARS-CoV-2 infectivity and Niemann-Pick disease type C, with therapeutic implications.

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.