INTRODUCTION: Epidermolysis bullosa (EB) describes a family of rare genetic blistering skin disorders. Various subtypes are clinically and genetically heterogeneous, and a lethal postpartum form of EB is the generalized severe junctional EB (gs-JEB). gs-JEB is mainly caused by premature termination codon (PTC) mutations in the skin anchor protein LAMB3 (laminin subunit beta-3) gene. The ribosome in majority of translational reads of LAMB3PTC mRNA aborts protein synthesis at the PTC signal, with production of a truncated, nonfunctional protein. This leaves an endogenous readthrough mechanism needed for production of functional full-length Lamb3 protein albeit at insufficient levels. Here, we report on the development of drugs targeting ribosomal protein L35 (rpL35), a ribosomal modifier for customized increase in production of full-length Lamb3 protein from a LAMB3PTC mRNA. METHODS: Molecular docking studies were employed to identify small molecules binding to human rpL35. Molecular determinants of small molecule binding to rpL35 were further characterized by titration of the protein with these ligands as monitored by nuclear magnetic resonance (NMR) spectroscopy in solution. Changes in NMR chemical shifts were used to map the docking sites for small molecules onto the 3D structure of the rpL35. RESULTS: Molecular docking studies identified 2 FDA-approved drugs, atazanavir and artesunate, as candidate small-molecule binders of rpL35. Molecular interaction studies predicted several binding clusters for both compounds scattered throughout the rpL35 structure. NMR titration studies identified the amino acids participating in the ligand interaction. Combining docking predictions for atazanavir and artesunate with rpL35 and NMR analysis of rpL35 ligand interaction, one binding cluster located near the N-terminus of rpL35 was identified. In this region, the nonidentical binding sites for atazanavir and artesunate overlap and are accessible when rpL35 is integrated in its natural ribosomal environment. CONCLUSION: Atazanavir and artesunate were identified as candidate compounds binding to ribosomal protein rpL35 and may now be tested for their potential to trigger a rpL35 ribosomal switch to increase production of full-length Lamb3 protein from a LAMB3PTC mRNA for targeted systemic therapy in treating gs-JEB.

• MeSH
• artesunát chemie   MeSH
• atazanavir sulfát chemie   MeSH
• epidermolysis bullosa junkční genetika   patologie   MeSH
• fyziologie kůže MeSH
• kůže patologie   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• molekuly buněčné adheze genetika   MeSH
• ribozomální proteiny metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• epidermolysis bullosa dystrophica diagnóza   genetika   patofyziologie   MeSH
• epidermolysis bullosa junkční diagnóza   genetika   patofyziologie   MeSH
• epidermolysis bullosa simplex diagnóza   genetika   patofyziologie   MeSH
• epidermolysis bullosa * diagnóza   genetika   patofyziologie   MeSH
• lidé MeSH
• sekvenční analýza DNA MeSH
• Check Tag
• lidé MeSH

Bartov syndróm, v literatúre známy aj pod akronymickým názvom CLAS (Congenital Localised Absence of Skin), prvý raz opísal Bart v roku 1966 ako vrodené lokalizované chýbanie kože, epidermolysis bullosa congenita a nechtové abnormity. V príspevku autori prezentujú makroskopický aj histologický nález nekroptického prípadu novorodenca s Bartovým syndrómom, s epidermolysis bullosa junctionalis a s atréziou pyloru, ktorý zomrel po 17 dňoch od narodenia a 13 dňoch od operácie stenózy pyloru.

Bart‘s syndrome, in literature also known under the name CLAS (Congenital Localised Absence of Skin), first described by Bart in 1966 as congenital localized absence of skin, epidermolysis bullosa congenita and nail abnormalities. The authors present a macroscopic and histological findings of a newborn with Bart‘s syndrome, with epidermolysis bullosa junctionalis and atresia pylori, who died 17 days after birth and 13 days after surgery for pyloric stenosis.

• MeSH
• epidermolysis bullosa junkční * diagnóza   genetika   patologie   MeSH
• kožní nemoci diagnóza   patologie   MeSH
• lidé MeSH
• mutace MeSH
• novorozenec MeSH
• pitva MeSH
• příčina smrti MeSH
• pylorus abnormality   patologie   MeSH
• syndrom MeSH
• vrozené vady MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• Publikační typ
• kazuistiky MeSH