Molecular dynamics simulation on the low sensitivity of mutants of NEDD-8 activating enzyme for MLN4924 inhibitor as a cancer drug

MLN4924 is an experimental cancer drug known as inhibitor of NEDD8-activating enzyme (NAE). This anti-tumor candidate is a selective small-molecule inhibitor of NAE which is conjugated to cullin protein on Cullin-RING ligases (CRLs). This covalent modification actives cullin complex to recruit an ubiquitin-charged E2 and leads to downstream target protein polyubiquitination and proteasomal degradation. MLN4924, which can form a covalent adduct with NEDD8, and block NAE at the first step in this pathway, has shown anti-tumor activity in many kinds of cancer cell lines and also xenograft models, including lung cancer, colon cancer, melanoma and lymphoma. The anti-tumor activity of MLN4924 results from inactivation of CLRs, which causes DNA re-replication and inhibition of nuclear factor (NF)-κB signaling, thus leading to cancer cell death. A mutation can reduce the enzyme’s sensitivity to MLN4924. Verma et al. in 2013 studied on molecular dynamics simulation of a mutant A171T and consequently found out that this mutation reduce MLN4924 interaction with DNA Binding site of enzyme as a result of reduction of enzyme affinity to ATP. One year later, in 2014, Wei Xu et al. carried out a research on inhibitor resistant cell lines and revealed that a couple of mutations so called Y352H and I310N leads to enzyme resistance to MLN4924 inhibitor, interestingly, the cause reported was the increase of enzyme affinity to ATP. As in Wei Xu et al. experiment the molecular dynamics simulation was not considered, present study is conducted to identify enzyme mutation mechanism by molecular dynamics approach using advantages of Gromacs software version 4.5.6.     

Imaging data in COVID-19 patients: focused on echocardiographic findings

To assess imaging data in COVID-19 patients and its association with clinical course and survival and 86 consecutive patients (52 males, 34 females, mean age?=?58.8 year) with documented COVID-19 infection were included. Seventy-eight patients (91%) were in severe stage of the disease. All patients underwent transthoracic echocardiography. Mean LVEF was 48.1% and mean estimated systolic pulmonary artery pressure (sPAP) was 27.9 mmHg. LV diastolic dysfunction was mildly abnormal in 49 patients (57.6%) and moderately abnormal in 7 cases (8.2%). Pericardial effusion was present in 5/86 (minimal in size in 3 cases and mild- moderate in 2). In 32/86 cases (37.2%), the severity of infection progressed from “severe” to “critical”. Eleven patients (12.8%) died. sPAP and computed tomography score were associated with disease progression (P value?=?0.002, 0.002 respectively). Tricuspid annular plane systolic excursion (TAPSE) was significantly higher in patients with no disease progression compared with those who deteriorated (P value?=?0.005). Pericardial effusion (minimal, mild or moderate) was detected more often in progressive disease (P?=?0.03). sPAP was significantly lower among survivors (P value?=?0.007). Echocardiographic findings (including systolic PAP, TAPSE and pericardial effusion), total CT score may have prognostic and therapeutic implication in COVID-19 patients.

     

Development trends for generation of single-chain antibody fragments

Recombinant antibodies are increasingly being employed as therapeutic agents especially in combination with anti-cancer drugs. The single-chain antibody fragments are small antigen-binding proteins which provide the most commonly used antibody formats for diagnostic and therapeutic purposes. These antibody fragments have more rapid tumor penetration and clearance from the serum relative to full-length monoclonal antibodies. There are in vitro antibody-display technologies such as phage display, cell surface display, ribosome display and mRNA display that can be used to isolate high specificity and affinity single-chain antibodies against a wide variety of targets. We review these strategies for generation of stable and active antibody fragments in the present article.     

Interactive protein network of FXIII-A1 in lipid rafts of activated and non-activated platelets

Lipid-rafts are defined as membrane microdomains enriched in cholesterol and glycosphingolipids within platelet plasma membrane. Lipid raft-mediated clot retraction requires factor XIII and other interacting proteins. The aim of this study was to investigate the proteins that interact with factor XIII in raft and non-raft domains of activated and non-activated platelet plasma membrane. By lipidomics analysis, we identified cholesterol- and sphingomyelin-enriched areas as lipid rafts. Platelets were activated by thrombin. Proteomics analysis provided an overview of the pathways in which proteins of rafts and non-rafts participated in the interaction network of FXIII-A1, a catalytic subunit of FXIII. “Platelet activation” was the principal pathway among KEGG pathways for proteins of rafts, both before and after activation. Network analysis showed four types of interactions (activation, binding, reaction, and catalysis) in raft and non-raft domains in interactive network of FXIII-A1. FXIII-A1 interactions with other proteins in raft domains and their role in homeostasis highlight the specialization of the raft domain in clot retraction via the Factor XIII protein network.