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

eLife ◽  
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.

scholarly journals The Development of a Novel Nanobody Therapeutic for SARS-CoV-2

2020 ◽  
Author(s):  
Gang Ye ◽  
Joseph P. Gallant ◽  
Christopher Massey ◽  
Ke Shi ◽  
Wanbo Tai ◽  
...  
Keyword(s):  
Low Cost ◽  
Structural Data ◽  
Phage Display Library ◽  
Pharmacokinetic Analysis ◽  
Viral Receptor ◽  
Single Domain Antibodies ◽  
High Yields ◽  
Conventional Antibody

AbstractCombating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a novel 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 out viral receptor ACE2. The lead drug possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD with a Kd of 15.7picomolar (∼3000 times more tightly than ACE2 did) and inhibited SARS-CoV-2 infection with an ND50 of 0.16microgram/milliliter (∼6000 times more potently than ACE2 did). Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy in hamsters subjected to SARS-CoV-2 infection. Unlike conventional antibody drugs, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented a greater than 10-day in vivo half-life efficacy and high tissue bioavailability. Nanosota-1C-Fc is a potentially effective and realistic solution to the COVID-19 pandemic.Impact statementPotent and low-cost Nanosota-1 drugs block SARS-CoV-2 infections both in vitro and in vivo and act both preventively and therapeutically.

scholarly journals Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1186
Author(s):  
Bárbara Pinto ◽  
Ana C. Henriques ◽  
Patrícia M. A. Silva ◽  
Hassan Bousbaa
Keyword(s):  
Cancer Research ◽  
Low Cost ◽  
Three Dimensional ◽  
3D Culture ◽  
Comprehensive Overview ◽  
Culture Techniques ◽  
Drug Candidates ◽  
In Vivo Testing

Most cancer biologists still rely on conventional two-dimensional (2D) monolayer culture techniques to test in vitro anti-tumor drugs prior to in vivo testing. However, the vast majority of promising preclinical drugs have no or weak efficacy in real patients with tumors, thereby delaying the discovery of successful therapeutics. This is because 2D culture lacks cell–cell contacts and natural tumor microenvironment, important in tumor signaling and drug response, thereby resulting in a reduced malignant phenotype compared to the real tumor. In this sense, three-dimensional (3D) cultures of cancer cells that better recapitulate in vivo cell environments emerged as scientifically accurate and low cost cancer models for preclinical screening and testing of new drug candidates before moving to expensive and time-consuming animal models. Here, we provide a comprehensive overview of 3D tumor systems and highlight the strategies for spheroid construction and evaluation tools of targeted therapies, focusing on their applicability in cancer research. Examples of the applicability of 3D culture for the evaluation of the therapeutic efficacy of nanomedicines are discussed.

scholarly journals Critical Considerations for the Design of Multi-Organ Microphysiological Systems (MPS)

2021 ◽  
Vol 9 ◽  
Author(s):  
Mridu Malik ◽  
Yang Yang ◽  
Parinaz Fathi ◽  
Gretchen J. Mahler ◽  
Mandy B. Esch
Keyword(s):  
Animal Models ◽  
Drug Toxicity ◽  
New Drugs ◽  
Drug Candidate ◽  
Preclinical Studies ◽  
Toxicity Screening ◽  
Drug Candidates ◽  
Microphysiological Systems

Identification and approval of new drugs for use in patients requires extensive preclinical studies and clinical trials. Preclinical studies rely on in vitro experiments and animal models of human diseases. The transferability of drug toxicity and efficacy estimates to humans from animal models is being called into question. Subsequent clinical studies often reveal lower than expected efficacy and higher drug toxicity in humans than that seen in animal models. Microphysiological systems (MPS), sometimes called organ or human-on-chip models, present a potential alternative to animal-based models used for drug toxicity screening. This review discusses multi-organ MPS that can be used to model diseases and test the efficacy and safety of drug candidates. The translation of an in vivo environment to an in vitro system requires physiologically relevant organ scaling, vascular dimensions, and appropriate flow rates. Even small changes in those parameters can alter the outcome of experiments conducted with MPS. With many MPS devices being developed, we have outlined some established standards for designing MPS devices and described techniques to validate the devices. A physiologically realistic mimic of the human body can help determine the dose response and toxicity effects of a new drug candidate with higher predictive power.

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

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.

scholarly journals Finding melanoma drugs through a probabilistic knowledge graph

2016 ◽  
Author(s):  
James P McCusker ◽  
Michel Dumontier ◽  
Rui Yan ◽  
Sylvia He ◽  
Jonathan S Dordick ◽  
...  
Keyword(s):  
Systems Biology ◽  
Probabilistic Methods ◽  
Drug Candidate ◽  
Knowledge Graph ◽  
Web Interface ◽  
Drug Candidates ◽  
Probabilistic Knowledge ◽  
Data Explosion

Metastatic cutaneous melanoma is an aggressive skin cancer with some progression-slowing treatments but no known cure. The omics data explosion has created many possible drug candidates, however filtering criteria remain challenging, and systems biology approaches have become fragmented with many disconnected databases. Using drug, protein, and disease interactions, we built an evidence-weighted knowledge graph of integrated interactions. Our knowledge graph-based system, ReDrugS, can be used via an API or web interface, and has generated 25 high quality melanoma drug candidates. We show that probabilistic analysis of systems biology graphs increases drug candidate quality compared to non-probabilistic methods. Four of the 25 candidates are novel therapies, three of which have been tested with other cancers. All other candidates have current or completed clinical trials, or have been studied in in vivo or in vitro. This approach can be used to identify candidate therapies for use in research or personalized medicine.

scholarly journals The Impact of Dosing Interval in a Novel Tandem Oral Dosing Strategy: Enhancing the Exposure of Low Solubility Drug Candidates in a Preclinical Setting

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Po-Chang Chiang ◽  
Sarah A. South ◽  
Steve P. Wene
Keyword(s):  
Resource Constraints ◽  
Drug Candidate ◽  
Time Interval ◽  
Drug Candidates ◽  
Safety Studies ◽  
Early Decision ◽  
Dosing Strategy ◽  
The Impact ◽  
Low Solubility

In drug discovery, time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical or pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity. This issue is more significant for efficacy and target safety studies where high drug exposures are desired. When solubility issues are confronted, enabling formulations are often required to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. Previously, we introduced a gastrointestinal (GI) transit time-based novel oral tandem dosing strategy that enhanced in vivo exposures in rats. In this study, a refined time interval versus dose theory was tested. The resulting in vivo exposures based on altering frequency and doses were compared, and significant impacts were found.

scholarly journals A Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as Potential Chemotherapeutic Agent: From Synthesis to In Vivo Studies

2019 ◽  
Author(s):  
Anna Notaro ◽  
Angelo Frei ◽  
Riccardo Rubbiani ◽  
Marta Jakubaszek ◽  
Uttara Basu ◽  
...  
Keyword(s):  
Chemotherapeutic Agent ◽  
Biological Properties ◽  
In Vivo Studies ◽  
Drug Candidate ◽  
Paramagnetic Resonance ◽  
In Vivo Models ◽  
Drug Candidates ◽  
X Ray Crystallography

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a surge for new chemotherapeutic drugs. More specifically, the discovery of new drug candidates able to overcome severe side effects, the occurrence of resistance and the inefficacy toward metastatic tumours is highly desirable. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely [Ru(DIP)2(sq)]PF6 (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated to the catecholate moiety. Several pieces of experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrate that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinised in vitro and in vivo, and the results highlight the tremendous potential of this complex as a chemotherapeutic agent against cancer. Ru-sq was notably found have a much higher cytotoxic activity than cisplatin on several cell lines (i.e. in the nanomolar range), and, contrary to cisplatin, to have mitochondrial disfunction as one of its modes of action. The multicellular targets of Ru-sq could potentially be the key to overcome one of the main drawbacks of cisplatin i.e. the occurrence of resistance. Moreover, Ru-sq exhibited impressing activity on Multi Cellular Tumour Spheroids (MCTS) model, leading to a growth inhibition of the tumour even 13 days after treatment (20 μM). Very importantly, using two different in vivo models, it could be demonstrated that this compound is extremely well-tolerated by mice and has a very promising activity, curing, in some cases, tumour-bearing mice.<br>

scholarly journals Active Component ofAntrodia cinnamomeaMycelia Targeting Head and Neck Cancer Initiating Cells through Exaggerated Autophagic Cell Death

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Ching-Wen Chang ◽  
Chien-Chih Chen ◽  
Meng-Ju Wu ◽  
Yu-Syuan Chen ◽  
Chin-Chu Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Active Component ◽  
Alternative Therapy ◽  
Drug Candidate ◽  
Aldh Activity ◽  
Drug Candidates

Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer. Previously, we identify head and neck cancer initiating cells (HN-CICs), which are highly tumorigenic and resistant to conventional therapy. Therefore, development of drug candidates that effectively target HN-CICs would benefit future head and neck cancer therapy. In this study, we first successfully screened for an active component, named YMGKI-1, from natural products ofAntrodia cinnamomeaMycelia (ACM), which can target the stemness properties of HNSCC. Treatment of YMGKI-1 significantly downregulated the aldehyde dehydrogenase (ALDH) activity, one of the characteristics of CIC in HNSCC cells. Additionally, the tumorigenic properties of HNSCC cells were attenuated by YMGKI-1 treatmentin vivo. Further, the stemness properties of HN-CICs, which are responsible for the malignancy of HNSCC, were also diminished by YMGKI-1 treatment. Strikingly, YMGKI-1 also effectively suppressed the cell viability of HN-CICs but not normal stem cells. Finally, YMGKI-1 induces the cell death of HN-CICs by dysregulating the exaggerated autophagic signaling pathways. Together, our results indicate that YMGKI-1 successfully lessens stemness properties and tumorigenicity of HN-CICs. These findings provide a new drug candidate from purified components of ACM as an alternative therapy for head and neck cancer in the future.

scholarly journals Finding melanoma drugs through a probabilistic knowledge graph

2017 ◽  
Vol 3 ◽  
pp. e106 ◽  
Author(s):  
James P. McCusker ◽  
Michel Dumontier ◽  
Rui Yan ◽  
Sylvia He ◽  
Jonathan S. Dordick ◽  
...  
Keyword(s):  
Systems Biology ◽  
Application Programming Interface ◽  
Probabilistic Methods ◽  
Drug Candidate ◽  
Knowledge Graph ◽  
Drug Candidates ◽  
Application Programming ◽  
Data Explosion

Metastatic cutaneous melanoma is an aggressive skin cancer with some progression-slowing treatments but no known cure. The omics data explosion has created many possible drug candidates; however, filtering criteria remain challenging, and systems biology approaches have become fragmented with many disconnected databases. Using drug, protein and disease interactions, we built an evidence-weighted knowledge graph of integrated interactions. Our knowledge graph-based system, ReDrugS, can be used via an application programming interface or web interface, and has generated 25 high-quality melanoma drug candidates. We show that probabilistic analysis of systems biology graphs increases drug candidate quality compared to non-probabilistic methods. Four of the 25 candidates are novel therapies, three of which have been tested with other cancers. All other candidates have current or completed clinical trials, or have been studied in in vivo or in vitro. This approach can be used to identify candidate therapies for use in research or personalized medicine.

scholarly journals Cryptotanshinone Inhibits the Growth of HCT116 Colorectal Cancer Cells Through Endoplasmic Reticulum Stress-Mediated Autophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojing Fu ◽  
Wenwen Zhao ◽  
Kangkang Li ◽  
Jingyi Zhou ◽  
Xuehong Chen
Keyword(s):  
Colorectal Cancer ◽  
Er Stress ◽  
Salvia Miltiorrhiza ◽  
Underlying Mechanism ◽  
Drug Candidate ◽  
Drug Candidates ◽  
Colorectal Cancer Cells ◽  
Sw620 Cells

Among cancers, colorectal cancer (CRC) has one of the highest annual incidence and death rates. Considering severe adverse reactions associated with classical chemotherapy medications, traditional Chinese medicines have become potential drug candidates. In the current study, the effects of cryptotanshinone (CPT), a major component of Salvia miltiorrhiza Bunge (Danshen) on CRC and underlying mechanism were explored. First of all, data from in vitro experiments and in vivo zebrafish models indicated that CPT selectively inhibited the growth and proliferation of HCT116 and SW620 cells while had little effect on SW480 cells. Secondly, both ER stress and autophagy were associated with CRC viability regulation. Interestingly, ER stress inhibitor and autophagy inhibitor merely alleviated cytotoxic effects on HCT116 cells in response to CPT stimulation, while have little effect on SW620 cells. The significance of apoptosis, autophagy and ER stress were verified by clinical data from CRC patients. In summary, the current study has revealed the anti-cancer effects of CPT in CRC by activating autophagy signaling mediated by ER stress. CPT is a promising drug candidate for CRC treatment.

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