Aminoacyl-tRNA synthetases classically regulate protein synthesis but some also engage in alternative signaling functions related to immune responses and angiogenesis. Threonyl-tRNA synthetase (TARS) is an autoantigen the autoimmune disorder myositis borrelidin, a potent inhibitor of TARS, inhibits We explored mechanistic link between these findings by testing whether TARS directly affects angiogenesis through inflammatory mediators. When human vascular endothelial cells were exposed tumor...

Abstract The polyketide natural product borrelidin displays antibacterial, antifungal, antimalarial, anticancer, insecticidal and herbicidal activities through the selective inhibition of threonyl-tRNA synthetase (ThrRS). How simultaneously attenuates bacterial growth suppresses a variety infections in plants animals is not known. Here we show, using X-ray crystal structures functional analyses, that single molecule occupies four distinct subsites within catalytic domain human ThrRSs. These...

Significance Malaria remains one of the main health threats in developing world, with staggering social and economic costs. Resistance to artemisins, pharmacological tool currently available against malaria, has been widely reported. Borrelidin, a natural compound that inhibits threonyl-tRNA synthetase, long studied for its antibacterial antiparasitic properties, but undesirable toxic effects prevented further clinical development. Here we present group borrelidin derivatives retain their...

An integrin-binding peptide derived from collagen IV prevents ligand-induced activation of multiple tyrosine kinase receptors and strongly suppresses ocular neovascularization vascular leakage.

Macrophages respond to signals in the microenvironment by changing their functional phenotypes, a process known as polarization. Depending on context, they acquire different patterns of transcriptional activation, cytokine expression and cellular metabolism which collectively constitute continuous spectrum two extremes are denoted classical (M1) alternative (M2) activation. To quantitatively decode underlying principles governing macrophage phenotypic polarization thereby harness its...

The angiopoietin (Ang)/Tie2 signaling pathway is essential for maintaining vascular homeostasis, and its dysregulation associated with several diseases. Interactions between Tie2 α5β1 integrin have emerged as part of this control; however, the mechanism incompletely understood. AXT107, a collagen IV-derived peptide, has strong antipermeability activity enabled elucidation previously undetermined mechanism. Previously, AXT107 was shown to inhibit VEGFR2 other growth factor via receptor...

Abstract While poly(lactic‐ co ‐glycolic acid)‐ block ‐polyethylene glycol (PLGA‐PEG) nanoparticles (NPs) can encapsulate drug cargos and prolong circulation times, they show nonspecific accumulation in off‐target tissues. Targeted delivery of drugs to tumor tissue vasculature is a promising approach for treating solid tumors while enhancing specificity reducing systemic toxicity. AXT050, collagen‐IV derived peptide with both antitumor antiangiogenic properties, shown bind tumor‐associated...

Abstract Aminoacyl-tRNA synthetases (AARSs) catalyze an early step in protein synthesis, but also regulate diverse physiological processes animal cells. These include angiogenesis and human threonyl-tRNA synthetase (TARS) represents a potent pro-angiogenic AARS. Angiogenesis stimulation can be blocked by the macrolide antibiotic borrelidin (BN), which exhibits broad spectrum toxicity that has discouraged deeper investigation. Recently, less toxic variant (BC194) was identified potently...

Abstract Hepatocyte growth factor (HGF) signaling through its receptor Met has been implicated in hepatocellular carcinoma tumorigenesis and progression. interaction with integrins is shown to modulate the downstream Akt ERK (extracellular-regulated kinase). In this study, we developed a mechanistically detailed systems biology model of HGF/Met pathway that incorporated specific interactions investigate efficacy integrin-binding peptide, AXT050, as monotherapy combination other therapeutics...

AXT107, a collagen-derived peptide that binds integrins αvβ3 and α5β1 with high affinity, suppresses vascular endothelial growth factor (VEGF) signaling, promotes angiopoietin 2-induced Tie2 activation, neovascularization (NV) leakage. Immunohistochemical staining for was markedly increased in NV compared normal retinal vessels. After intravitreous injection of there no an anti-AXT107 antibody on vessels but robust co-localized α5β1. Likewise, after injection, fluorescein amidite-labeled...

Aminoacyl-tRNA synthetases (ARSs) enhance the fidelity of protein synthesis through multiple mechanisms, including hydrolysis adenylate and cleavage misacylated tRNA. Alanyl-tRNA synthetase (AlaRS) limits misacylation with glycine serine by use a dedicated editing domain, mutation in this activity has been genetically linked to mouse model progressive neurodegenerative disease. Using free-standing Pyrococcus horikoshii AlaX domain complexed as both Ser-tRNA(Ala) Ala-tRNA(Ala) substrates,...

Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive disease with limited treatment options. Recently, the combination of immune checkpoint inhibitor (ICI) atezolizumab (anti-PD-L1) nab-paclitaxel was approved following clinical trial that showed response rates in at least 43% patients. While this approval marks major advance TNBC it may be possible to improve efficacy ICI therapies through further modulation suppressive tumor microenvironment (TIME). Several factors...

Persistent inflammation is a complication associated with many ocular diseases. Changes in vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes eye, vascular leakage, perfusion. Here, we report anti-inflammatory activity for AXT107, non-RGD, 20-mer αvβ3 α5β1 integrin-binding peptide that blocks endothelial growth factor (VEGF)-signaling activates tyrosine kinase immunoglobulin EGF-like domains 2 (Tie2) using normally inhibitory ligand...

Abstract Chemokinostatin-1 (CKS1) is a 24-mer peptide originally discovered as an anti-angiogenic derived from the CXCL1 chemokine. Here, we demonstrate that CKS1 acts not only but also oncolytic due to its structural and physical properties. induced both necrotic apoptotic cell death specifically in cancer cells while showing minimal toxicity non-cancerous cells. Mechanistically, disrupted membrane of quickly after treatment activated pathway at later time points. Furthermore, immunogenic...

// Mustafa A. Barbhuiya 1, * , Adam C. Mirando 2, Brian W. Simons 3 Ghali Lemtiri-Chlieh 1 Jordan J. Green 2 Aleksander S. Popel Niranjan B. Pandey and Phuoc T. Tran Department of Radiation Oncology Molecular Sciences, Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins School Medicine, Baltimore, MD, USA Biomedical Engineering, University Medical Oncology, Centre Urology, The Brady Urological Institute, These authors have contributed equally to this work Correspondence to: Tran, email:...

It was observed that rat fetuses exposed to chemical retardants (polybrominated diphenyl‐ethers, or PBDE's) showed postnatally increased preference for non‐caloric sweetened water. In the present study we investigated whether young growing rats PBDE's would consume more of a calorie containing sucrose solution then non‐treated controls. Forty day‐old male and female (n = 24) were treated daily with either (18 mg/kg) control treatment corn oil by gavage. Animals given access two drinking...

Abstract Chemokinostatin-1 (CKS1) is a 24-mer peptide originally discovered as an anti-angiogenic derived from the CXCL1 chemokine. Here, we demonstrate that CKS1 acts not only but also oncolytic due to its structural and physical properties. induced both necrotic apoptotic cell death specifically in cancer cells while showing minimal toxicity non-cancerous cells. Mechanistically, disrupted membrane of quickly after treatment activated pathway at later time points. Furthermore, immunogenic...

Abstract In mammalian systems, several aminoacyl-tRNA synthetases are known to have distinct non-canonical functionality. For the first time, we demonstrate that human threonyl-tRNA synthetase (TARS) induces angiogenesis through endothelial cell signaling, and this induction can be blocked by borrelidin derivative compound BC194. Upon stimulation with vascular growth factor (VEGF) or tumor necrosis factor-alpha (TNF-α), cells secrete TARS into extracellular space. Extracellular BC194...