scholarly journals Precursors of Viral Proteases as Distinct Drug Targets

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1981
Author(s):  
Taťána Majerová ◽  
Pavel Novotný
Keyword(s):  
Enzyme Activity ◽  
Host Cell ◽  
Binding Sites ◽  
Drug Target ◽  
Drug Targets ◽  
Mechanisms Of Action ◽  
Protease Domain ◽  
Viral Protease ◽  
Detailed Understanding ◽  
Viral Proteases

Viral proteases are indispensable for successful virion maturation, thus making them a prominent drug target. Their enzyme activity is tightly spatiotemporally regulated by expression in the precursor form with little or no activity, followed by activation via autoprocessing. These cleavage events are frequently triggered upon transportation to a specific compartment inside the host cell. Typically, precursor oligomerization or the presence of a co-factor is needed for activation. A detailed understanding of these mechanisms will allow ligands with non-canonical mechanisms of action to be designed, which would specifically modulate the initial irreversible steps of viral protease autoactivation. Binding sites exclusive to the precursor, including binding sites beyond the protease domain, can be exploited. Both inhibition and up-regulation of the proteolytic activity of viral proteases can be detrimental for the virus. All these possibilities are discussed using examples of medically relevant viruses including herpesviruses, adenoviruses, retroviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, and coronaviruses.

scholarly journals Machine intelligence design of 2019-nCoV drugs

2020 ◽  
Author(s):  
Kaifu Gao ◽  
Duc Duy Nguyen ◽  
Rui Wang ◽  
Guo-Wei Wei
Keyword(s):  
Binding Sites ◽  
Drug Target ◽  
Machine Intelligence ◽  
Respiratory Syndrome Virus ◽  
Viral Protease ◽  
Inhibitor Binding ◽  
Potential Effectiveness ◽  
Sequence Identity ◽  
Hiv Drugs ◽  
Network Complex

AbstractWuhan coronavirus, called 2019-nCoV, is a newly emerged virus that infected more than 9692 people and leads to more than 213 fatalities by January 30, 2020. Currently, there is no effective treatment for this epidemic. However, the viral protease of a coronavirus is well-known to be essential for its replication and thus is an effective drug target. Fortunately, the sequence identity of the 2019-nCoV protease and that of severe-acute respiratory syndrome virus (SARS-CoV) is as high as 96.1%. We show that the protease inhibitor binding sites of 2019-nCoV and SARS-CoV are almost identical, which means all potential anti-SARS-CoV chemotherapies are also potential 2019-nCoV drugs. Here, we report a family of potential 2019-nCoV drugs generated by a machine intelligence-based generative network complex (GNC). The potential effectiveness of treating 2019-nCoV by using some existing HIV drugs is also analyzed.

scholarly journals Identification of Peptide Antagonists to Thioredoxin Glutathione Reductase ofSchistosoma japonicum

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Li-Jun Song ◽  
Jia-Huang Li ◽  
Xu-Ren Yin ◽  
Wei Zhang ◽  
Yi Jin ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Glutathione Reductase ◽  
Binding Sites ◽  
Drug Target ◽  
Promising Candidate ◽  
Phage Display Peptide Library ◽  
Novel Drugs ◽  
Alternative Drug ◽  
Substrate Binding Sites ◽  
Thioredoxin Glutathione Reductase

Schistosomiasis is one of the world’s major public health problems. Praziquantel is currently the only effective drug against schistosomiasis. As resistance of praziquantel has emerged in some endemic areas, development of new antischistosomal agents should be a high priority. In this study, a phage display peptide library was used for screening for peptide antagonists of thioredoxin glutathione reductase ofSchistosoma japonicum(SjTGR), which has been identified as an alternative drug target. Three rounds of panning produced four different fusion phages. ELISA proved that all four phages could bind to SjTGR. One peptide, JIPDys1 (aa, WPHNWWPHFKVK), reduced enzyme activity of SjTGR by more than 50%. 2μM of the synthesized peptide of JIPDys1 inhibited the activity of TrxR, GR, and Grx of SjTGR by 32.5%, 100%, and 100%, respectively. The IC50values of the synthetic peptide JIPDys1 for TrxR, GR, and Grx were 3.67μM, 0.11μM, and 0.97μM, respectively. Based on computer simulation, it appeared that JIPDys1 binds to the substrate binding sites of glutathione reductase (GR) and glutaredoxin (Grx). Our data show that the peptide, JIPDys1 (aa, WPHNWWPHFKVK), is a promising candidate to develop novel drugs againstS. japonicumwhich acts by binding with SjTGR and reduces enzyme activity of SjTGR.

scholarly journals LiP-Quant, an automated chemoproteomic approach to identify drug targets in complex proteomes

2019 ◽  
Author(s):  
Ilaria Piazza ◽  
Nigel Beaton ◽  
Roland Bruderer ◽  
Thomas Knobloch ◽  
Crystel Barbisan ◽  
...  
Keyword(s):  
Small Molecule ◽  
Binding Sites ◽  
Drug Target ◽  
Drug Targets ◽  
Target Identification ◽  
Limited Proteolysis ◽  
Drug Binding ◽  
Homologous Proteins ◽  
Protein Targets ◽  
Drug Target Identification

Chemoproteomics is a key technology to characterize the mode of action of drugs, as it directly identifies the protein targets of bioactive compounds and aids in developing optimized small-molecule compounds. Current unbiased approaches cannot directly pinpoint the interaction surfaces between ligands and protein targets. To address his limitation we have developed a new drug target deconvolution approach based on limited proteolysis coupled with mass spectrometry that works across species including human cells (LiP-Quant). LiP-Quant features an automated data analysis pipeline and peptide-level resolution for the identification of any small-molecule binding sites, Here we demonstrate drug target identification by LiP-Quant across compound classes, including compounds targeting kinases and phosphatases. We demonstrate that LiP-Quant estimates the half maximal effective concentration (EC50) of compound binding sites in whole cell lysates. LiP-Quant identifies targets of both selective and promiscuous drugs and correctly discriminates drug binding to homologous proteins. We finally show that the LiP-Quant technology identifies targets of a novel research compound of biotechnological interest.

scholarly journals Elucidating drug targets and mechanisms of action by genetic screens in mammalian cells

2017 ◽  
Vol 53 (53) ◽  
pp. 7162-7167 ◽  
Author(s):  
Martin Kampmann
Keyword(s):  
Mammalian Cells ◽  
Drug Target ◽  
Drug Targets ◽  
Drug Response ◽  
Target Identification ◽  
Mechanisms Of Action ◽  
Genetic Screens ◽  
Crispr Interference ◽  
Genome Wide ◽  
Drug Target Identification

Genome-wide CRISPR interference (CRISPRi) screens in mammalian cells enable drug target identification and uncover genes controlling drug response.

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment

2020 ◽  
Vol 20 (6) ◽  
pp. 444-465 ◽  
Author(s):  
Jessica Ceramella ◽  
Domenico Iacopetta ◽  
Alexia Barbarossa ◽  
Anna Caruso ◽  
Fedora Grande ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Drug Targets ◽  
Mechanisms Of Action ◽  
Biological Pathways ◽  
G Protein Coupled Receptors ◽  
Ability To Act ◽  
Different Types ◽  
Activity Of Enzymes ◽  
Intercalating Agents ◽  
G Protein Coupled

Protein Kinases (PKs) are a heterogeneous family of enzymes that modulate several biological pathways, including cell division, cytoskeletal rearrangement, differentiation and apoptosis. In particular, due to their crucial role during human tumorigenesis and cancer progression, PKs are ideal targets for the design and development of effective and low toxic chemotherapeutics and represent the second group of drug targets after G-protein-coupled receptors. Nowadays, several compounds have been claimed to be PKs inhibitors, and some of them, such as imatinib, erlotinib and gefitinib, have already been approved for clinical use, whereas more than 30 others are in various phases of clinical trials. Among them, some natural or synthetic carbazole-based molecules represent promising PKs inhibitors due to their capability to interfere with PK activity by different mechanisms of action including the ability to act as DNA intercalating agents, interfere with the activity of enzymes involved in DNA duplication, such as topoisomerases and telomerases, and inhibit other proteins such as cyclindependent kinases or antagonize estrogen receptors. Thus, carbazoles can be considered a promising this class of compounds to be adopted in targeted therapy of different types of cancer.

SARS-CoV-2 Biology Insights, Part I. Genome-wide structure and druggability: literature review (Preprint)

2020 ◽  
Author(s):  
Laura Lafon-Hughes
Keyword(s):  
Side Effects ◽  
Literature Review ◽  
Host Cell ◽  
Nucleoside Analogs ◽  
Viral Proteins ◽  
Therapeutic Strategies ◽  
Adverse Side Effects ◽  
Viral Proteases ◽  
Genome Wide ◽  
Therapeutic Alternatives

BACKGROUND COVID-19 pandemic prompts the study of coronavirus biology and search of putative therapeutic strategies. OBJECTIVE To compare SARS-CoV-2 genome-wide structure and proteins with other coronaviruses, focusing on putative coronavirus-specific or SARS-CoV-2 specific therapeutic designs. METHODS The genome-wide structure of SARS-CoV-2 was compared to that of SARS and other coronaviruses in order to gain insights, doing a literature review through Google searches. RESULTS There are promising therapeutic alternatives. Host cell targets could be modulated to hamper viral replication, but targeting viral proteins directly would be a better therapeutic design, since fewer adverse side effects would be expected. CONCLUSIONS Therapeutic strategies (Figure 1) could include the modulation of host targets (PARPs, kinases) , competition with G-quadruplexes or nucleoside analogs to hamper RDRP. The nicest anti-CoV options include inhibitors of the conserved essential viral proteases and drugs that interfere ribosome slippage at the -1 PRF site.

scholarly journals Protease Inhibitors as Antiviral Agents

1998 ◽  
Vol 11 (4) ◽  
pp. 614-627 ◽  
Author(s):  
A. K. Patick ◽  
K. E. Potts
Keyword(s):  
Protease Inhibitors ◽  
Viral Infections ◽  
Critical Role ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Structural Proteins ◽  
Viral Protease ◽  
Virus Particles ◽  
Viral Proteases ◽  
Viral Polyprotein

SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

scholarly journals 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

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