Search results for "Cysteine Endopeptidase"
showing 10 items of 90 documents
Computer-guided drug repurposing: Identification of trypanocidal activity of clofazimine, benidipine and saquinavir
2015
In spite of remarkable advances in the knowledge on Trypanosoma cruzi biology, no medications to treat Chagas disease have been approved in the last 40 years and almost 8 million people remain infected. Since the public sector and non-profit organizations play a significant role in the research efforts on Chagas disease, it is important to implement research strategies that promote translation of basic research into the clinical practice. Recent international public-private initiatives address the potential of drug repositioning (i.e. finding second or further medical uses for known-medications) which can substantially improve the success at clinical trials and the innovation in the pharmac…
Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population
2010
BackgroundAlbeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis.Methodology/principal findingsImmunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendroc…
In Silico Insights into the SARS CoV-2 Main Protease Suggest NADH Endogenous Defences in the Control of the Pandemic Coronavirus Infection
2020
COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used for Ebola infection). This work proposes a repurposing process using a database containing approximately 8000 known drugs in synergy structure- and ligand-based studies by means of the molecular docking and descriptor-based protocol. The proposed in silico findings identified new potential SARS CoV-2 main protease (MPRO) inhibitors that fit in the catalytic binding site of SARS CoV-2 MPRO. Several sel…
Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure-Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X-ray Crystal…
2013
The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 subs…
Tuning and Predicting Biological Affinity: Aryl Nitriles as Cysteine Protease Inhibitors
2012
A series of aryl nitrile-based ligands were prepared to investigate the effect of their electrophilicity on the affinity against the cysteine proteases rhodesain and human cathepsin L. Density functional theory calculations provided relative reactivities of the nitriles, enabling prediction of their biological affinity and cytotoxicity and a clear structure-activity relationship.
Evidence for substrate binding-induced zwitterion formation in the catalytic Cys-His dyad of the SARS-CoV main protease.
2014
The coronavirus main protease (M(pro)) represents an attractive drug target for antiviral therapy of coronavirus (CoV) infections, including severe acute respiratory syndrome (SARS). The SARS-CoV M(pro) and related CoV proteases have several distinct features, such as an uncharged Cys-His catalytic dyad embedded in a chymotrypsin-like protease fold, that clearly separate these enzymes from archetypical cysteine proteases. To further characterize the catalytic system of CoV main proteases and to obtain information about improved inhibitors, we performed comprehensive simulations of the proton-transfer reactions in the SARS-CoV M(pro) active site that lead to the Cys(-)/His(+) zwitterionic st…
Sortase A Inhibitors: Recent Advances and Future Perspectives
2015
Here, we describe the most promising small synthetic organic compounds that act as potent Sortase A inhibitors and cater the potential to be developed as antivirulence drugs. Sortase A is a polypeptide of 206 amino acids, which catalyzes two sequential reactions: (i) thioesterification and (ii) transpeptidation. Sortase A is involved in the process of bacterial adhesion by anchoring LPXTG-containing proteins to lipid II. Sortase A inhibitors do not affect bacterial growth, but they restrain the virulence of pathogenic bacterial strains, thereby preventing infections caused by Staphylococcus aureus or other Gram-positive bacteria. The efficacy of the most promising inhibitors needs to be com…
Structure, interdomain dynamics, and pH-dependent autoactivation of pro-rhodesain, the main lysosomal cysteine protease from African trypanosomes
2021
AbstractRhodesain is the lysosomal cathepsin L-like cysteine protease ofT. brucei rhodesiense, the causative agent of Human African Trypanosomiasis. The enzyme is essential for the proliferation and pathogenicity of the parasite as well as its ability to overcome the blood-brain barrier of the host. Lysosomal cathepsins are expressed as zymogens with an inactivating pro-domain that is cleaved under acidic conditions. A structure of the uncleaved maturation intermediate from a trypanosomal cathepsin L-like protease is currently not available. We thus established the heterologous expression ofT. brucei rhodesiensepro-rhodesain inE. coliand determined its crystal structure. The trypanosomal pr…
Candidate Targets for Hepatitis C Virus-Specific Antiviral Therapy
1997
The hepatitis C virus (HCV) was identified as the major causative agent of posttransfusion and community-acquired non-A, non-B hepatitis throughout the world. It is an enveloped virus with a plus-strand RNA genome encoding a polyprotein of about 3,010 amino acids. This polyprotein is cleaved co- and posttranslationally into mature viral proteins by host cell signal peptidases and 2 viral enzymes designated the NS2-3 proteinase and the NS3/4A proteinase complex. It is assumed that virus replication takes place in a membrane-associated complex containing at least 2 viral enzymatic activities: the NS3 nucleoside triphosphatase (NTPase)/helicase and the NS5B RNA-dependent RNA polymerase (RdRp).…
Effects of E-64 (cysteine-proteinase inhibitor) and pepstatin (aspartyl-proteinase inhibitor) on metastasis formation in mice with mammary and ovaria…
1994
The effects of E-64 (Cathepsin B and L inhibitor) and Pepstatin A (Cathepsin D inhibitor) on spontaneous and experimental metastasis formation were investigated in mice with MCa mammary carcinoma, M5076 ovarian sarcoma and L1210 leukemia. Pepstatin induced a marked decrease in the number of spontaneous metastasis in MCa or M5076 tumor bearing mice. This phenomenon was also noted with E-64 but only in M5076 tumor bearing mice. On the other hand, both these agents were unable to prevent the formation of experimental metastasis in mice injected i.v. with L1210, MCa or M5076 tumor cells or with tumor cells in which Cathepsin B, L and D activities were inhibited by a 24 hour continuous exposure …