47. VENOMICS: High-throughput peptidomics and transcriptomics of animal venoms for discovery of novel therapeutic peptides

Peptide therapeutics has made tremendous progress in the past decade. Many of the inherent weaknesses of peptides which hampered their development as therapeutics are now more or less effectively tackled with recent scientific and technological advancements in integrated drug discovery settings. These include recent developments in synthetic organic chemistry, high-throughput recombinant production strategies, highresolution analytical methods, high-throughput screening options, ingenious drug delivery strategies and novel formulation preparations. Here, we will briefly describe the key methodologies and strategies used in the therapeutic peptide development processes with selected examples of the most recent developments in the field. The aim of this review is to highlight the viable options a medicinal chemist may consider in order to improve a specific pharmacological property of interest in a peptide lead entity and thereby rationally assess the therapeutic potential this class of molecules possesses while they are traditionally (and incorrectly) considered ‘undruggable’.

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637 Integrative high throughput analysis for the identification of novel therapeutic targets in breast cancer

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(10)71437-3 ◽

2010 ◽

Vol 8 (5) ◽

pp. 161

Keyword(s):

Breast Cancer ◽

High Throughput ◽

Therapeutic Targets ◽

High Throughput Analysis ◽

Throughput Analysis ◽

Novel Therapeutic

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PF581 FUNCTIONAL HIGH-THROUGHPUT SCREENING FOR IDENTIFICATION OF NOTCH1 DOWNSTREAM EFFECTORS AS NOVEL THERAPEUTIC TARGETS IN MULTIPLE MYELOMA

HemaSphere ◽

10.1097/01.hs9.0000560612.37732.0e ◽

2019 ◽

Vol 3 (S1) ◽

pp. 242

Author(s):

D.S. Maichl ◽

F. Ziouti ◽

S. Schmidt ◽

C.P. Ade ◽

F. Jundt

Keyword(s):

Multiple Myeloma ◽

High Throughput ◽

High Throughput Screening ◽

Therapeutic Targets ◽

Downstream Effectors ◽

Novel Therapeutic

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HemoNet: Predicting hemolytic activity of peptides with integrated feature learning

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720021500219 ◽

2021 ◽

pp. 2150021

Author(s):

Adiba Yaseen ◽

Sadaf Gull ◽

Naeem Akhtar ◽

Imran Amin ◽

Fayyaz Minhas

Keyword(s):

Amino Acids ◽

Hemolytic Activity ◽

Cross Validation ◽

Feature Learning ◽

Predictive Performance ◽

Peptide Sequence ◽

Therapeutic Peptides ◽

Wet Lab ◽

Novel Therapeutic

Quantifying the hemolytic activity of peptides is a crucial step in the discovery of novel therapeutic peptides. Computational methods are attractive in this domain due to their ability to guide wet-lab experimental discovery or screening of peptides based on their hemolytic activity. However, existing methods are unable to accurately model various important aspects of this predictive problem such as the role of N/C-terminal modifications, D- and L- amino acids, etc. In this work, we have developed a novel neural network-based approach called HemoNet for predicting the hemolytic activity of peptides. The proposed method captures the contextual importance of different amino acids in a given peptide sequence using a specialized feature embedding in conjunction with SMILES-based fingerprint representation of N/C-terminal modifications. We have analyzed the predictive performance of the proposed method using stratified cross-validation in comparison with previous methods, non-redundant cross-validation as well as validation on external peptides and clinical antimicrobial peptides. Our analysis shows the proposed approach achieves significantly better predictive performance (AUC-ROC of 88%) in comparison to previous approaches (HemoPI and HemoPred with AUC-ROC of 73%). HemoNet can be a useful tool in the search for novel therapeutic peptides. The python implementation of the proposed method is available at the URL: https://github.com/adibayaseen/HemoNet.

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A truncated RHAMM protein for discovering novel therapeutic peptides

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2018.09.018 ◽

2018 ◽

Vol 26 (18) ◽

pp. 5194-5203 ◽

Cited By ~ 1

Author(s):

Alexandra Hauser-Kawaguchi ◽

Cornelia Tolg ◽

Teresa Peart ◽

Mark Milne ◽

Eva A. Turley ◽

...

Keyword(s):

Therapeutic Peptides ◽

Novel Therapeutic

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Development of high-throughput screening assays for profiling snake venom Phospholipase A2 activity after high-resolution chromatographic fractionation

10.1101/2020.01.20.912758 ◽

2020 ◽

Author(s):

Kristina B.M. Still ◽

Julien Slagboom ◽

Sarah Kidwai ◽

Chunfang Xie ◽

Bastiaan Eisses ◽

...

Keyword(s):

Fatty Acid ◽

High Resolution ◽

High Throughput ◽

High Throughput Screening ◽

Proinflammatory Mediators ◽

Ph Indicators ◽

Snake Venom Phospholipase ◽

Screening Assays ◽

Animal Venoms ◽

Phospholipase A2 Activity

AbstractMany organisms, ranging from plants to mammals, contain phospholipase A2 enzymes (PLA2s), which catalyze the production of lysophospholipids and fatty acid proinflammatory mediators. PLA2s are also common constituents of animal venoms, including bees, scorpions and snakes, and they cause a wide variety of toxic effects including neuro-, myo-, cyto-, and cardio-toxicity, anticoagulation and edema. The aim of this study was to develop a generic method for profiling enzymatically active PLA2s in snake venoms after chromatographic separation. For this, low-volume high-throughput assays for assessment of enzymatic PLA2 activity were evaluated and optimized. Subsequently, the assays were incorporated into a nanofractionation platform that combines high-resolution fractionation of crude venoms by liquid chromatography (LC) with bioassaying in 384-well plate format, and parallel mass spectrometric (MS) detection for toxin identification. The miniaturized assays developed are based on absorbance or fluorescence detection (respectively, using cresol red or fluorescein as pH indicators) to monitor the pH drop associated with free fatty acid formation by enzymatically active PLA2s. The methodology was demonstrated for assessment of PLA2 activity profiles of venoms from the snake species Bothrops asper, Echis carinatus, Echis coloratus, Echis ocellatus, Oxyuranus scutellatus and Daboia russelii russelii.

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Identification of potent and safe antiviral therapeutic candidates against SARS-CoV-2

10.1101/2020.07.06.188953 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xia Xiao ◽

Conghui Wang ◽

De Chang ◽

Ying Wang ◽

Xiaojing Dong ◽

...

Keyword(s):

Cell Fusion ◽

High Throughput ◽

Severe Disease ◽

Therapeutic Agents ◽

Effective Concentration ◽

Therapeutic Window ◽

Safety Index ◽

Human Coronavirus ◽

Us Fda ◽

Novel Therapeutic

AbstractCOVID-19 pandemic has infected millions of people with mortality exceeding 300,000. There is an urgent need to find therapeutic agents that can help clear the virus to prevent the severe disease and death. Identifying effective and safer drugs can provide with more options to treat the COVID-19 infections either alone or in combination. Here we performed a high throughput screen of approximately 1700 US FDA approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 24 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, and merfloquine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating wide therapeutic window compared to hydroxychloroquine which had safety index of 22 in similar experiments. Mechanistically, five of the effective compounds were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA approved compounds can provide much needed therapeutic options that we urgently need in the midst of the pandemic.

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