Defensin-5

SignificanceWe report the development of peptidomimetic antibiotics derived from a natural antimicrobial peptide, human α-defensin 5. By engaging multiple bacterial targets, the lead compound is efficacious in vitro and in vivo against bacteria with highly inducible antibiotic resistance, promising a useful therapeutic agent for the treatment of infections caused by antibiotic-resistant bacteria.

Paneth cells (PCs) are located at the base of small intestinal crypts and secrete the α-defensins, human α-defensin 5 (HD-5) and human α-defensin 6 (HD-6) in response to bacterial, cholinergic and other stimuli. The α-defensins are broad-spectrum microbicides that play critical roles in controlling gut microbiota and maintaining intestinal homeostasis. Inflammatory bowel disease, including ulcerative colitis and Crohn's disease (CD), is a complicated autoimmune disorder. The pathogenesis of CD involves genetic factors, environmental factors and microflora. Surprisingly, with regard to genetic factors, many susceptible genes and pathogenic pathways of CD, including nucleotide-binding oligomerization domain 2 (NOD2), autophagy-related 16-like 1 (ATG16L1), immunity-related guanosine triphosphatase family M (IRGM), wingless-related integration site (Wnt), leucine-rich repeat kinase 2 (LRRK2), histone deacetylases (HDACs), caspase-8 (Casp8) and X-box-binding protein-1 (XBP1), are relevant to PCs. As the underlying mechanisms are being unravelled, PCs are identified as the central element of CD pathogenesis, integrating factors among microbiota, intestinal epithelial barrier dysfunction and the immune system. In the present review, we demonstrate how these genes and pathways regulate CD pathogenesis via their action on PCs and what treatment modalities can be applied to deal with these PC-mediated pathogenic processes.

Corona virus disease 2019 (Covid-19), a pandemia emerged recently, caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). The receptor for corona virus and influenza A is the mucosal cell membrane protein angiotensin converting enzyme 2 (ACE2), which is abundant on the membrane of alveolar cells and enterocytes. Viral spike protein 1 (S1) is the ligand, with an affinity of 14.7 nM to the receptor. The main port of entry for the virus is the upper respiratory tract, and the diagnosis is usually by PCR of the viral RNA with nasal and pharyngeal swab test. Human defensin 5 (HDEF5) is a protein encoded by the DEFA gene, secreted by Paneth cells in the small intestine and by granules of neutrophils. It has an affinity of 39.3 nM to ACE2, much higher than that of the corona S1. HDEF5 may also attach to glycosylated Corona S1 protein, make its efficiency even better. The issues to be investigated are the affinity of HDEF5 to S1 protein, the ability of recombinant HDEF5 function in attaching both ACE2 and S1, and the feasibility to perform aerosol spray of this protein. In addition, safety and efficiency should be studied in phases I, II and II clinical protocols. Thus, an aerosol spray of HDEF5 given through the nose and throat, once to several times a day, may be a very efficient approach to prevent infection with SARA-CoV-2 as well as influenza A.