Structure-based screening of drug candidates targeting the SARS-CoV-2 envelope protein

The COVID-19 (coronavirus disease 2019) pandemic is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). SARS-CoV-2 produces a small hydrophobic envelope (E) protein which shares high homology with SARS-CoV E protein. By patch-clamp recording, the E protein is demonstrated to be a cation-selective ion channel. Furthermore, the SARS-CoV-2 E protein can be blocked by a SARS-CoV E protein inhibitor hexamethylene amiloride. Using structural model and virtual screening, another E protein inhibitor AZD5153 is discovered. AZD5153 is a bromodomain protein 4 inhibitor against hematologic malignancies in clinical trial. The E protein amino acids Phe23 and Val29 are key determinants for AZD5153 sensitivity. This study provides two promising lead compounds and a functional assay of SARS-CoV-2 E protein for the future drug candidate discovery.

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A broadly neutralizing biparatopic Nanobody protects mice from lethal challenge with SARS-CoV-2 variants of concern

10.1101/2021.08.08.455562 ◽

2021 ◽

Author(s):

Teresa R. Wagner ◽

Daniel Schnepf ◽

Julius Beer ◽

Karin Klingel ◽

Natalia Ruetalo ◽

...

Keyword(s):

Lethal Dose ◽

Survival Rates ◽

Drug Candidate ◽

Lethal Challenge ◽

Drug Candidates ◽

High Affinity ◽

Neutralizing Capacity ◽

Future Drug

The ongoing COVID-19 pandemic and the frequent emergence of new SARS-CoV-2 variants of concern (VOCs), requires continued development of fast and effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nb) specific for the receptor-binding domain (RBD) of SARS-CoV-2, which are now being used as biparatopic Nbs (bipNbs) to investigate their potential as future drug candidates. Following detailed in vitro characterization, we chose NM1267 as the most promising candidate showing high affinity binding to several recently described SARS-CoV-2 VOCs and strong neutralizing capacity against a patient isolate of B.1.351 (Beta). To assess if bipNb NM1267 confers protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice were treated by intranasal route before infection with a lethal dose of SARS-CoV-2. NM1267-treated mice showed significantly reduced disease progression, increased survival rates and secreted less infectious virus via their nostrils. Histopathological analyses and in situ hybridization further revealed a drastically reduced viral load and inflammatory response in lungs of NM1267-treated mice. These data suggest, that bipNb NM1267 is a broadly active and easily applicable drug candidate against a variety of emerging SARS-CoV-2 VOCs.

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Synthesis of Pyrazolofuropyrazine via One-Pot SNAr Reaction and Intramolecular Direct C–H Arylation

Synthesis ◽

10.1055/s-0036-1591885 ◽

2018 ◽

Vol 50 (07) ◽

pp. 1493-1498 ◽

Cited By ~ 3

Author(s):

Shinichiro Fuse ◽

Hiroyuki Nakamura ◽

Megumi Inaba ◽

Shinichi Sato ◽

Manjusha Joshi

Keyword(s):

Drug Discovery ◽

Rapid Development ◽

Ring System ◽

Biologically Active ◽

Drug Candidate ◽

One Pot ◽

Ring Systems ◽

Drug Candidates ◽

Fused Ring ◽

Snar Reaction

Fused-ring systems containing heterocycles are attractive templates for drug discovery. Biologically active 6-5-5+6 fused-ring systems that possess heterocycles are available, but these require a relatively large number of synthetic steps for preparation. Therefore, pyrazolofuropyrazine was designed as a 6-5-5+6 ring system template that incorporates ready accessibility for drug discovery. Pyrazolofuropyrazines were successfully constructed in only a few steps via one-pot SNAr reaction/intramolecular C–H direct arylation. As a drug candidate, pyrazolofuropyrazine has earned a favorable LogP, although significant biological activity has yet to be established; the ready accessibility of pyrazolofuropyrazine template, however, offers an opportunity for the rapid development of promising new drug candidates.

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Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

Current Neuropharmacology ◽

10.2174/1385272823666191021124443 ◽

2020 ◽

Vol 18 (5) ◽

pp. 348-407 ◽

Cited By ~ 4

Author(s):

Vanessa Silva Gontijo ◽

Flávia P. Dias Viegas ◽

Cindy Juliet Cristancho Ortiz ◽

Matheus de Freitas Silva ◽

Caio Miranda Damasio ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Rational Design ◽

Brain Regions ◽

Molecular Hybridization ◽

Drug Candidate ◽

New Paradigm ◽

New Approach ◽

Biological Targets ◽

Drug Candidates ◽

Biochemical Pathways

Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.

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Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

Frontiers in Pharmacology ◽

10.3389/fphar.2021.625678 ◽

2021 ◽

Vol 12 ◽

Author(s):

Charlotte Kern ◽

Verena Schöning ◽

Carlos Chaccour ◽

Felix Hammann

Keyword(s):

Drug Repurposing ◽

Antiviral Effect ◽

Drug Candidate ◽

Appreciable Effect ◽

Viral Kinetics ◽

Future Drug ◽

Dosing Regimens ◽

Clinical Trial Results

Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3–0.6 log units and exposure by 8.8–22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

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Preclinical Assessment of a Novel CDC7 Inhibitor: Genomewide RNAi Screening Identifies Unique Synergetic and Resistance Genes,

Blood ◽

10.1182/blood.v118.21.3570.3570 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3570-3570

Author(s):

Nancy Liu-Sullivan ◽

Bhavneet Bhinder ◽

David Shum ◽

Christina Ramirez ◽

Constantin Radu ◽

...

Keyword(s):

Kinase Inhibitor ◽

De Novo ◽

Conflicts Of Interest ◽

Drug Candidate ◽

Microscopy Imaging ◽

Drug Candidates ◽

Shrna Library ◽

Ubiquitin Proteasome ◽

Screening Platform ◽

Drug Responsiveness

Abstract Abstract 3570 Despite extensive drug discovery efforts, drug-candidate failure and patients relapsing in the clinic remain as persistent problems. While insufficient drug-gene engagement leads to drug failure, de novo escape mutations give rise to patients relapsing, calling the need for systemic studies on how genes influence drug responsiveness. Towards this end, we have explored a functional short hairpin RNA (shRNA) based genomic screening platform aimed at interrogating drug-gene engagement and assessing its consequences on signaling pathways. We propose this concept as a novel way to evaluate drug candidates prior to clinical trials enabling liability assessment and predicting clinical outcome. We took advantage of the arrayed shRNA library produced in lentiviral particles and characterized by several obvious advantageous features including shRNA targeting one hairpin at a time and on the fly high content whole well microscopy imaging analysis. We carried out three parallel genomewide shRNA screens in the absence or presence of the novel CDC7 kinase inhibitor (MSK-777) at its IC20 and IC50 and have identified several gene candidates that influence MSK-777 sensitivity and resistance. These include synergizers that enhance MSK-777 sensitivity and rescuers that confer MSK-777 resistance. IPA analysis mapped clusters of these hits to multiple major pathways among them were the NF-kB pathway, the ubiquitin-proteasome pathway, DNA replication, and several epigenetic regulatory genes. We will present and discuss this concept together with the emerging pathways as a means to identify both key therapeutic targets and biomarkers of sensitivity and resistance. Thus, allowing for not only a broader applicability of assessing candidate genes that modulate specific drug agents, but also for the identification of a tailored and more efficacious therapeutic regimen to treat cancer. Disclosures: No relevant conflicts of interest to declare.

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Antileishmanial potential of alkaloids isolated from plants: an integrative review

Research Society and Development ◽

10.33448/rsd-v9i10.9334 ◽

2020 ◽

Vol 9 (10) ◽

pp. e9119109334

Author(s):

Andreza do Socorro Silva da Veiga ◽

Heliton Patrick Cordovil Brígido ◽

Sandro Percário ◽

Andrey Moacir do Rosário Marinho ◽

Maria Fâni Dolabela

Keyword(s):

Therapeutic Response ◽

Leishmania Parasite ◽

Drug Candidate ◽

Inclusion Criteria ◽

Scientific Papers ◽

Future Drug ◽

Chemical Studies ◽

Leishmania Promastigotes ◽

Toxic Potential ◽

Therapeutic Alternatives

Leishmaniasis treatment is often carried out with drugs of high toxic potential and high cost, and satisfactory therapeutic response is not usually observed. In this context, searching for therapeutic alternatives is urgent. This study seeks to evaluate the antileishmanial potential of alkaloids from plants. The search for scientific papers occurred at Pubmed, CAPES Journal Portal (PPC), Virtual Health Library (VHL) and COCHRANE using the descriptors: alkaloid and antileishmanial. The inclusion criteria were studies about alkaloids isolated from plants and tested against Leishmania parasite. A total of 805 publications were found in Pubmed, 825 in PPC, 4 in VHL and none in COCRHANE. After reading the titles and abstracts, articles containing other biological evaluations (350), chemical studies such as docking and material characterizations (388), evaluation of extracts and fractions activities (406) which did not fit in this research or were in duplicate (377) were excluded. Acridone and all the naphthylisoquinolinic and tetrahydroisoquinolinic alkaloids were active or moderately active against Leishmania promastigotes or amastigotes, and indolizidine was active against both forms. The β-carbolines were inactive or moderately active against Leishmania promastigotes, with the exception of flavopereirine. The indolizidine alkaloid was the most promising as a future drug candidate, since it was very active against both forms of Leishmania.

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Biomedical Graph Visualizer for Identifying Drug Candidates

10.1101/2020.11.27.368811 ◽

2020 ◽

Author(s):

Ashton Teng ◽

Blanca Villanueva ◽

Derek Jow ◽

Shih-Cheng (Mars) Huang ◽

Samantha N. Piekos ◽

...

Keyword(s):

Drug Development ◽

De Novo ◽

Drug Candidate ◽

Knowledge Graph ◽

Major Barrier ◽

Drug Candidates ◽

Novel Treatments ◽

Computational Discovery ◽

Complex Relationships ◽

User Friendly

1.AbstractMillions of Americans suffer from illnesses with non-existent or ineffective drug treatment. Identifying plausible drug candidates is a major barrier to drug development due to the large amount of time and resources required; approval can take years when people are suffering now. While computational tools can expedite drug candidate discovery, these tools typically require programming expertise that many biologists lack. Though biomedical databases continue to grow, they have proven difficult to integrate and maintain, and non-programming interfaces for these data sources are scarce and limited in capability. This creates an opportunity for us to present a suite of user-friendly software tools to aid computational discovery of novel treatments through de novo discovery or repurposing. Our tools eliminate the need for researchers to acquire computational expertise by integrating multiple databases and offering an intuitive graphical interface for analyzing these publicly available data. We built a computational knowledge graph focused on biomedical concepts related to drug discovery, designed visualization tools that allow users to explore complex relationships among entities in the graph, and served these tools through a free and user-friendly web interface. We show that users can conduct complex analyses with relative ease and that our knowledge graph and algorithms recover approved repurposed drugs. Our evaluation indicates that our method provides an intuitive, easy, and effective toolkit for discovering drug candidates. We show that our toolkit makes computational analysis for drug development more accessible and efficient and ultimately plays a role in bringing effective treatments to all patients.Our application is hosted at: https://biomedical-graph-visualizer.wl.r.appspot.com/

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Modeling of SARS-CoV-2 treatment effects for informed drug repurposing

10.21203/rs.3.rs-153281/v2 ◽

2021 ◽

Author(s):

Charlotte Kern ◽

Verena Schöning ◽

Carlos Chaccour ◽

Felix Hammann

Keyword(s):

Drug Repurposing ◽

Antiviral Effect ◽

Drug Candidate ◽

Appreciable Effect ◽

Viral Kinetics ◽

Future Drug ◽

Dosing Regimens ◽

Clinical Trial Results

Abstract Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide.We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3-0.6 log units and exposure by 8.8-22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

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A simple method to determine the elimination half-life of drugs displaying noncumulative toxicity

10.1101/761585 ◽

2019 ◽

Author(s):

Deepesh Nagarajan ◽

Preetham Venkatesh ◽

Chandrani Thakur ◽

Akshay Datey ◽

Nagasuma Chandra ◽

...

Keyword(s):

Half Life ◽

Mass Spectrometric ◽

Drug Candidate ◽

Spectrometric Method ◽

Mass Spectrometric Method ◽

Simple Method ◽

Drug Candidates ◽

Elimination Half ◽

The Many

ABSTRACTThe pharmacokinetic characterization of a drug, especially the determination of its biological half-life, is an essential step during the early phases of drug development. An adequate half-life is amongst the many properties needed for selecting a drug candidate for clinical trials. Conversely, drug candidates possessing inadequate half-lives may be modified or eliminated from the drug discovery pipeline altogether. Several methods exist for determining the half-lives of drugs, namely HPLC, fluorescence assays, radioassays, radioimmunoassays, and elemental mass spectrometric assays. However, all these techniques are resource and labor-intensive, and cannot be used for the high-throughput half-life determination of hundreds of drug candidates. Here, we describe TOXHL: a simple technique to determine the half-lives of compounds displaying noncumulative toxicity. To calculate the half life, TOXHL only relies on the survival outcomes of three experiments performed on an animal model: an acute toxicity experiment, a cumulative toxicity experiment, and a multi-dose experiment at different dosing intervals. As a proof of concept, we use TOXHL to determine the peritoneal half-life of Ω76, an antimicrobial peptide. The half-life of Ω76 determined by TOXHL is in good agreement with results from a standard mass spectrometric method, validating this approach.

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The Development of Nanosota-1 as anti-SARS-CoV-2 nanobody drug candidates

eLife ◽

10.7554/elife.64815 ◽

2021 ◽

Vol 10 ◽

Author(s):

Gang Ye ◽

Joseph Gallant ◽

Jian Zheng ◽

Christopher Massey ◽

Ke Shi ◽

...

Keyword(s):

Low Cost ◽

Structural Data ◽

Phage Display Library ◽

Drug Candidate ◽

Pharmacokinetic Analysis ◽

Viral Receptor ◽

Drug Candidates ◽

Single Domain Antibodies ◽

High Yields

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that Nanosota-1 bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking viral receptor ACE2. The lead drug candidate possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD ~3000 times more tightly than ACE2 did and inhibited SARS-CoV-2 pseudovirus ~160 times more efficiently than ACE2 did. Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented an excellent in vivo stability and a high tissue bioavailability. As effective and inexpensive drug candidates, Nanosota-1 may contribute to the battle against COVID-19.

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