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Fulltext Druggable targets of SARS-CoV-2 and treatment opportunities for COVID-19

Faheem, Kumar BK, Sekhar KVGC, Kunjiappan S, Jamalis J, Balaña-Fouce R, et al.

Bioorg Chem, 2020 Nov;104:104269.
PMID: 32947136 DOI: 10.1016/j.bioorg.2020.104269

COVID-19 caused by the novel SARS-CoV-2 has been declared a pandemic by the WHO is causing havoc across the entire world. As of May end, about 6 million people have been affected, and 367 166 have died from COVID-19. Recent studies suggest that the SARS-CoV-2 genome shares about 80% similarity with the SARS-CoV-1 while their protein RNA dependent RNA polymerase (RdRp) shares 96% sequence similarity. Remdesivir, an RdRp inhibitor, exhibited potent activity against SARS-CoV-2 in vitro. 3-Chymotrypsin like protease (also known as Mpro) and papain-like protease, have emerged as the potential therapeutic targets for drug discovery against coronaviruses owing to their crucial role in viral entry and host-cell invasion. Crystal structures of therapeutically important SARS-CoV-2 target proteins, namely, RdRp, Mpro, endoribonuclease Nsp15/NendoU and receptor binding domain of CoV-2 spike protein has been resolved, which have facilitated the structure-based design and discovery of new inhibitors. Furthermore, studies have indicated that the spike proteins of SARS-CoV-2 use the Angiotensin Converting Enzyme-2 (ACE-2) receptor for its attachment similar to SARS-CoV-1, which is followed by priming of spike protein by Transmembrane protease serine 2 (TMPRSS2) which can be targeted by a proven inhibitor of TMPRSS2, camostat. The current treatment strategy includes repurposing of existing drugs that were found to be effective against other RNA viruses like SARS, MERS, and Ebola. This review presents a critical analysis of druggable targets of SARS CoV-2, new drug discovery, development, and treatment opportunities for COVID-19.

Matched MeSH terms: Drug Discovery*
Fulltext Natural Bioactive Thiazole-Based Peptides from Marine Resources: Structural and Pharmacological Aspects

Dahiya R, Dahiya S, Fuloria NK, Kumar S, Mourya R, Chennupati SV, et al.

Mar Drugs, 2020 Jun 24;18(6).
PMID: 32599909 DOI: 10.3390/md18060329

Peptides are distinctive biomacromolecules that demonstrate potential cytotoxicity and diversified bioactivities against a variety of microorganisms including bacteria, mycobacteria, and fungi via their unique mechanisms of action. Among broad-ranging pharmacologically active peptides, natural marine-originated thiazole-based oligopeptides possess peculiar structural features along with a wide spectrum of exceptional and potent bioproperties. Because of their complex nature and size divergence, thiazole-based peptides (TBPs) bestow a pivotal chemical platform in drug discovery processes to generate competent scaffolds for regulating allosteric binding sites and peptide-peptide interactions. The present study dissertates on the natural reservoirs and exclusive structural components of marine-originated TBPs, with a special focus on their most pertinent pharmacological profiles, which may impart vital resources for the development of novel peptide-based therapeutic agents.

Matched MeSH terms: Drug Discovery
Establishing metastatic patient-derived xenograft model for colorectal cancer

Zhang Y, Lee SH, Wang C, Gao Y, Li J, Xu W

Jpn J Clin Oncol, 2020 Jun 24.
PMID: 32579167 DOI: 10.1093/jjco/hyaa089

BACKGROUND: Patient-derived xenograft model is a powerful and promising tool for drug discovery and cancer biology studies. The application of previous metastatic colorectal cancer models has been greatly limited by its low success rate and long time to develop metastasis. Therefore, in this study, we aim to describe an optimized protocol for faster establishment of colorectal cancer metastatic patient-derived xenograft mouse models.
METHODS: Smaller micro tissues (˂150 μm in diameter) mixed with Matrigel were engrafted subcutaneously into NSG mice to generate the passage 1 (P1) patient-derived xenograft. The micro tumours from P1 patient-derived xenograft were then excised and orthotopically xenografted into another batch of NSG mice to generate a metastatic colorectal cancer patient-derived xenograft, P2. Haematoxylin and eosin and immunohistochemistry staining were performed to compare the characters between patient-derived xenograft tumours and primary tumours.
RESULTS: About 16 out of 18 P1 xenograft models successfully grew a tumour for 50.8 ± 5.1 days (success rate 89.9%). Six out of eight P1 xenograft models originating from metastatic patients successfully grew tumours in the colon and metastasized to liver or lung in the NSG recipients for 60.9 ± 4.5 days (success rate 75%). Histological examination of both P1 and P2 xenografts closely resembled the histological architecture of the original patients' tumours. Immunohistochemical analysis revealed similar biomarker expression levels, including CDH17, Ki-67, active β-catenin, Ki-67 and α smooth muscle actin when compared with the original patients' tumours. The stromal components that support the growth of patient-derived xenograft tumours were of murine origin.
CONCLUSIONS: Metastatic patient-derived xenograft mouse model could be established with shorter time and higher success rate. Although the patient-derived xenograft tumours were supported by the stromal cells of murine origin, they retained the dominant characters of the original patient tumours.

Matched MeSH terms: Drug Discovery
Fulltext Isoniazid Conjugated Magnetic Nanoparticles Loaded with Amphotericin B as a Potent Antiamoebic Agent against Acanthamoeba castellanii

Iqbal K, Abdalla SAO, Anwar A, Iqbal KM, Shah MR, Anwar A, et al.

Antibiotics (Basel), 2020 May 25;9(5).
PMID: 32466210 DOI: 10.3390/antibiotics9050276

The pathogenic free-living amoeba, Acanthamoeba castellanii, is responsible for a rare but deadly central nervous system infection, granulomatous amoebic encephalitis and a blinding eye disease called Acanthamoeba keratitis. Currently, a combination of biguanides, amidine, azoles and antibiotics are used to manage these infections; however, the host cell cytotoxicity of these drugs remains a challenge. Furthermore, Acanthamoeba species are capable of transforming to the cyst form to resist chemotherapy. Herein, we have developed a nano drug delivery system based on iron oxide nanoparticles conjugated with isoniazid, which were further loaded with amphotericin B (ISO-NPs-AMP) to cause potent antiamoebic effects against Acanthamoeba castellanii. The IC50 of isoniazid conjugated with magnetic nanoparticles and loaded with amphotericin B was found to be 45 μg/mL against Acanthamoeba castellanii trophozoites and 50 μg/mL against cysts. The results obtained in this study have promising implications in drug discovery as these nanomaterials exhibited high trophicidal and cysticidal effects, as well as limited cytotoxicity against rat and human cells.

Matched MeSH terms: Drug Discovery
Translational genomics and recent advances in oral squamous cell carcinoma

Chai AWY, Lim KP, Cheong SC

Semin Cancer Biol, 2020 04;61:71-83.
PMID: 31542510 DOI: 10.1016/j.semcancer.2019.09.011

Oral squamous cell carcinomas (OSCC) are a heterogeneous group of cancers arising from the mucosal lining of the oral cavity. A majority of these cancers are associated with lifestyle risk habits including smoking, excessive alcohol consumption and betel quid chewing. Cetuximab, targeting the epidermal growth factor receptor was approved for the treatment of OSCC in 2006, and remains the only molecular targeted therapy available for OSCC. Here, we reviewed the current findings from genomic analyses of OSCC and discuss how these studies inform on the biological mechanisms underlying OSCC. Exome sequencing revealed that the significantly mutated genes are mainly tumour suppressors. Mutations in FAT1, CASP8, CDKN2A, and NOTCH1 are more frequently found in OSCC when compared to non-OSCC head and neck cancers and other squamous cell carcinomas, and HRAS and PIK3CA are the only significantly mutated oncogenes. The distribution of these mutations also differs in populations with distinct risk habits. Gene expression-based molecular classification showed that OSCC can be divided into distinct subtypes and these have a preferential response to different types of therapies, suggesting that these classifications could have clinical implications. More recently, with the approval of checkpoint inhibitors for the treatment of cancers including OSCC, genomics studies also dissected the genetic signatures of the immune compartment to delineate immune-active and -exhausted subtypes that could inform on the immune status of OSCC patients and guide the development of novel therapies to improve response to immunotherapy. Taken together, genomics studies are informing on the biology of both the epithelial and stromal compartments underlying OSCC development, and we discuss the opportunities and challenges in using these to derive clinical benefit for OSCC patients.

Matched MeSH terms: Drug Discovery
Could bacteriophages isolated from the sewage be the solution to methicillin-resistant Staphylococcus aureus?

Tan CS, Aqiludeen NA, Tan R, Gowbei A, Mijen AB, Santhana Raj L, et al.

Med J Malaysia, 2020 03;75(2):110-116.
PMID: 32281590

INTRODUCTIONS: The emergence of multidrug-resistant bacteria such as Methicillin-Resistant Staphylococcus aureus (MRSA) complicates the treatment of the simplest infection. Although glycopeptides such as vancomycin still proves to be effective in treating MRSA infections, the emergence of vancomycin-resistant strains limits the long term use of this antibiotic. Bacteriophages are ubiquitous bacterial viruses which is capable of infecting and killing bacteria including its antibiotic-resistant strains. Bactericidal bacteriophages use mechanisms that is distinct from antibiotics and is not affected by the antibioticresistant phenotypes.
OBJECTIVES: The study was undertaken to evaluate the possibility to isolate bacteriolytic bacteriophages against S.aureus from raw sewage water and examine their efficacy as antimicrobial agents in vitro.
METHODS: Bacteriophages were isolated from the raw sewage using the agar overlay method. Isolated bacteriophages were plaque purified to obtain homogenous bacteriophage isolates. The host range of the bacteriophages was determined using the spot test assay against the 25 MRSA and 36 MSSA isolates obtained from the Sarawak General Hospital. Staphylococcus saprophyticus, Staphylococcus sciuri and Staphylococcus xylosus were included as non-SA controls. The identity of the bacteriophages was identified via Transmission Electron Microscopy and genomic size analysis. Their stability at different pH and temperature were elucidated.
RESULTS: A total of 10 lytic bacteriophages infecting S.aureus were isolated and two of them namely ΦNUSA-1 and ΦNUSA-10 from the family of Myoviridae and Siphoviridae respectively exhibited exceptionally broad host range against >80% of MRSA and MSSA tested. Both bacteriophages were specific to S.aureus and stable at both physiologic pH and temperature.
CONCLUSION: This study demonstrated the abundance of S.aureus specific bacteriophages in raw sewage. Their high virulence against both MSSA and MRSA is an excellent antimicrobial characteristic which can be exploited for bacteriophage therapy against MRSA.

Matched MeSH terms: Drug Discovery/methods
Current progress in antimalarial pharmacotherapy and multi-target drug discovery

Tibon NS, Ng CH, Cheong SL

Eur J Med Chem, 2020 Feb 15;188:111983.
PMID: 31911292 DOI: 10.1016/j.ejmech.2019.111983

Discovery and development of antimalarial drugs have long been dominated by single-target therapy. Continuous effort has been made to explore and identify different targets in malaria parasite crucial for the malaria treatment. The single-target drug therapy was initially successful, but it was later supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has warranted a review of current antimalarial pharmacotherapy. This has led to the development of the new concept of covalent biotherapy, in which two or more pharmacophores are chemically bound to produce hybrid antimalarial drugs with multi-target functionalities. Herein, the review initially details the current pharmacotherapy for malaria as well as the conventional and novel targets of importance identified in the malaria parasite. Then, the rationale of multi-targeted therapy for malaria, approaches taken to develop the multi-target antimalarial hybrids, and the examples of hybrid molecules are comprehensively enumerated and discussed.

Matched MeSH terms: Drug Discovery*
Fulltext Biological Activities of Snowdrop (Galanthus spp., Family Amaryllidaceae)

Kong CK, Low LE, Siew WS, Yap WH, Khaw KY, Ming LC, et al.

Front Pharmacol, 2020;11:552453.
PMID: 33679383 DOI: 10.3389/fphar.2020.552453

Snowdrop is an iconic early spring flowering plant of the genus Galanthus (Amaryllidaceae). Galanthus species (Galanthus spp.) are economically important plants as ornaments. Galanthus spp has gained significance scientific and commercial interest due to the discovery of Galanthamine as symptomatic treatment drug for Alzhiermer disease. This review aims to discuss the bioactivities of Galanthus spp including anticholinesterase, antimicrobial, antioxidant and anticancer potential of the extracts and chemical constituents of Galanthus spp. This review highlights that Galanthus spp. as the exciting sources for drug discovery and nutraceutical development.

Matched MeSH terms: Drug Discovery
Fulltext Sinensetin: An Insight on Its Pharmacological Activities, Mechanisms of Action and Toxicity

Han Jie L, Jantan I, Yusoff SD, Jalil J, Husain K

Front Pharmacol, 2020;11:553404.
PMID: 33628166 DOI: 10.3389/fphar.2020.553404

Sinensetin, a plant-derived polymethoxylated flavonoid found in Orthosiphon aristatus var. aristatus and several citrus fruits, has been found to possess strong anticancer activities and a variety of other pharmacological benefits and promising potency in intended activities with minimal toxicity. This review aims to compile an up-to-date reports of published scientific information on sinensetin pharmacological activities, mechanisms of action and toxicity. The present findings about the compound are critically analyzed and its prospect as a lead molecule for drug discovery is highlighted. The databases employed for data collection are mainly through Google Scholar, PubMed, Scopus and Science Direct. In-vitro and in-vivo studies showed that sinensetin possessed strong anticancer activities and a wide range of pharmacological activities such as anti-inflammatory, antioxidant, antimicrobial, anti-obesity, anti-dementia and vasorelaxant activities. The studies provided some insights on its several mechanisms of action in cancer and other disease states. However, more detail mechanistic studies are needed to understand its pharmacological effects. More in vivo studies in various animal models including toxicity, pharmacokinetic, pharmacodynamic and bioavailability studies are required to assess its efficacy and safety before submission to clinical studies. In this review, an insight on sinensetin pharmacological activities and mechanisms of action serves as a useful resource for a more thorough and comprehensive understanding of sinensetin as a potential lead candidate for drug discovery.

Matched MeSH terms: Drug Discovery
Fulltext Cytotoxic and anticancer properties of the Malaysian mangrove pit viper (Trimeresurus purpureomaculatus) venom and its disintegrin (purpureomaculin)

Tan CH, Liew JL, Navanesan S, Sim KS, Tan NH, Tan KY

J Venom Anim Toxins Incl Trop Dis, 2020;26:e20200013.
PMID: 32742279 DOI: 10.1590/1678-9199-JVATITD-2020-0013

Background: The Asiatic pit vipers from the Trimeresurus complex are medically important venomous snakes. These pit vipers are often associated with snakebite that leads to fatal coagulopathy and tissue necrosis. The cytotoxic venoms of Trimeresurus spp.; however, hold great potential for the development of peptide-based anticancer drugs.
Methods: This study investigated the cytotoxic effect of the venom from Trimeresurus purpureomaculatus, the mangrove pit viper (also known as shore pit viper) which is native in Malaysia, across a panel of human cancer cell lines from breast, lung, colon and prostate as well as the corresponding normal cell lines of each tissue.
Results: The venom exhibited dose-dependent cytotoxic activities on all cell lines tested, with median inhibition concentrations (IC50) ranging from 0.42 to 6.98 µg/mL. The venom has a high selectivity index (SI = 14.54) on breast cancer cell line (MCF7), indicating that it is significantly more cytotoxic toward the cancer than to normal cell lines. Furthermore, the venom was fractionated using C18 reversed-phase high-performance liquid chromatography and the anticancer effect of each protein fraction was examined. Fraction 1 that contains a hydrophilic low molecular weight (approximately 7.5 kDa) protein was found to be the most cytotoxic and selective toward the breast cancer cell line (MCF7). The protein was identified using liquid chromatography-tandem mass spectrometry as a venom disintegrin, termed purpureomaculin in this study.
Conclusion: Taken together, the findings revealed the potent and selective cytotoxicity of a disintegrin protein isolated from the Malaysian T. purpureomaculatus venom and suggested its anticancer potential in drug discovery.

Matched MeSH terms: Drug Discovery
COVID-19: Underpinning Research for Detection, Therapeutics, and Vaccines Development

Aljabali AAA, Bakshi HA, Satija S, Metha M, Prasher P, Ennab RM, et al.

Pharm Nanotechnol, 2020;8(4):323-353.
PMID: 32811406 DOI: 10.2174/2211738508999200817163335

BACKGROUND: The newly emerged coronavirus SARS-CoV-2, first reported in December 2019, has infected about five and a half million people globally and resulted in nearly 9063264 deaths until the 24th of June 2020. Nevertheless, the highly contagious virus has instigated an unimaginably rapid response from scientific and medical communities.
OBJECTIVES: Pioneering research on molecular mechanisms underlying the viral transmission, molecular pathogenicity, and potential treatments will be highlighted in this review. The development of antiviral drugs specific to SARS-CoV-2 is a complicated and tedious process. To accelerate scientific discoveries and advancement, researchers are consolidating available data from associated coronaviruses into a single pipeline, which can be readily made available to vaccine developers.
METHODS: In order to find studies evaluating the COVID-19 virus epidemiology, repurposed drugs and potential vaccines, web searches and bibliographical bases have been used with keywords that matches the content of this review.
RESULTS: The published results of SARS-CoV-2 structures and interactomics have been used to identify potential therapeutic candidates. We illustrate recent publications on SARS-CoV-2, concerning its molecular, epidemiological, and clinical characteristics, and focus on innovative diagnostics technologies in the production pipeline. This objective of this review is to enhance the comprehension of the unique characteristics of SARS-CoV-2 and strengthen future control measures.
Lay Summary: An innovative analysis is evaluating the nature of the COVID-19 pandemic. The aim is to increase knowledge of possible viral detection methods, which highlights several new technology limitations and advantages. We have assessed some drugs currently for patients (Lopinavir, Ritonavir, Anakinra and Interferon beta 1a), as the feasibility of COVID-19 specific antivirals is not presently known. The study explores the race toward vaccine development and highlights some significant trials and candidates in various clinical phases. This research addresses critical knowledge gaps by identifying repurposed drugs currently under clinical trials. Findings will be fed back rapidly to the researchers interested in COVID 19 and support the evidence and potential of possible therapeutics and small molecules with their mode of action.

Matched MeSH terms: Drug Discovery*
Fulltext Distribution of plant species with potential therapeutic effect in area of the Universiti Teknologi MARA (UiTM), Kuala Pilah campus

Rosli Noormi, Raba’atun Adawiyah Shamsuddin, Anis Raihana Abdullah, Hidayah Yahaya, Liana Mohd Zulkamal, Muhammad Amar Rosly, et al.

Journal of Academia Universiti Teknologi MARA Negeri Sembilan, 2020;8(2):48-57.
MyJurnal

Knowledge of species richness and distribution is decisive for the composition of conservation areas. Plants typically contain many bioactive compounds are used for medicinal purposes for several disease treatment. This study aimed to identify the plant species distribution in area of UiTM Kuala Pilah, providing research scientific data and to contribute to knowledge of the use of the plants as therapeutic resources. Three quadrat frames (1x1 m), which was labeled as Set 1, 2 and 3 was developed, in each set consists of 4 plots (A, B, C and D). Characteristics of plant species were recorded, identified and classified into their respective groups. Our findings show that the most representative classes were Magnoliopsida with the total value of 71.43%, followed by Liliopsida (17.86%) and Lecanoromycetes (10.71%). A total of 28 plant species belonging to 18 families were identified in all sets with the largest family of Rubiaceae. The most distribution species are Desmodium triflorum, Dactyloctenium aegyptium, Flavoparmelia caperata, Xanthoria elegans and Phlyctis argena. Most of the plant possesses their potential to treat skin diseases, fever, ulcers and diabetes as well as digestive problems with their antimicrobial, anti-inflammatory and antioxidant properties. This study suggests that study site and plant species can be delineated as an important area to preserve these therapeutic resources. Finally, this study could also be useful for preliminary screening of potential therapeutic plant found in the study area and useful for the researchers in the pursuit of novel drug discovery.

Matched MeSH terms: Drug Discovery
Mechanisms of Antimicrobial Resistance (AMR) and Alternative Approaches to Overcome AMR

Moo CL, Yang SK, Yusoff K, Ajat M, Thomas W, Abushelaibi A, et al.

Curr Drug Discov Technol, 2020;17(4):430-447.
PMID: 30836923 DOI: 10.2174/1570163816666190304122219

Antimicrobials are useful compounds intended to eradicate or stop the growth of harmful microorganisms. The sustained increase in the rates of antimicrobial resistance (AMR) worldwide is worrying and poses a major public health threat. The development of new antimicrobial agents is one of the critical approaches to overcome AMR. However, in the race towards developing alternative approaches to combat AMR, it appears that the scientific community is falling behind when pitched against the evolutionary capacity of multi-drug resistant (MDR) bacteria. Although the "pioneering strategy" of discovering completely new drugs is a rational approach, the time and effort taken are considerable, the process of drug development could instead be expedited if efforts were concentrated on enhancing the efficacy of existing antimicrobials through: combination therapies; bacteriophage therapy; antimicrobial adjuvants therapy or the application of nanotechnology. This review will briefly detail the causes and mechanisms of AMR as background, and then provide insights into a novel, future emerging or evolving strategies that are currently being evaluated and which may be developed in the future to tackle the progression of AMR.

Matched MeSH terms: Drug Discovery
Exploring Antimicrobials from the Flora and Fauna of Marine: Opportunities and Limitations

Venkateskumar K, Parasuraman S, Chuen LY, Ravichandran V, Balamurgan S

Curr Drug Discov Technol, 2020;17(4):507-514.
PMID: 31424372 DOI: 10.2174/1570163816666190819141344

About 95% of earth living space lies deep below the ocean's surface and it harbors extraordinary diversity of marine organisms. Marine biodiversity is an exceptional reservoir of natural products, bioactive compounds, nutraceuticals and other potential compounds of commercial value. Timeline for the development of the drug from a plant, synthetic and other alternative sources is too lengthy. Exploration of the marine environment for potential bioactive compounds has gained focus and huge opportunity lies ahead for the exploration of such vast resources in the ocean. Further, the evolution of superbugs with increasing resistance to the currently available drugs is alarming and it needs coordinated efforts to resolve them. World Health Organization recommends the need and necessity to develop effective bioactive compounds to combat problems associated with antimicrobial resistance. Based on these factors, it is imperative to shift the focus towards the marine environment for potential bioactive compounds that could be utilized to tackle antimicrobial resistance. Current research trends also indicate the huge strides in research involving marine environment for drug discovery. The objective of this review article is to provide an overview of marine resources, recently reported research from marine resources, challenges, future research prospects in the marine environment.

Matched MeSH terms: Drug Discovery/methods*
Discovery and Development of Novel Anti-fungal Peptides Against Foodspoiling Fungi

Muhialdin BJ, Algboory HL, Mohammed NK, Kadum H, Hussin ASM, Saari N, et al.

Curr Drug Discov Technol, 2020;17(4):553-561.
PMID: 31309892 DOI: 10.2174/1570163816666190715120038

BACKGROUND: Despite the extensive research carried out to develop natural antifungal preservatives for food applications, there are very limited antifungal agents available to inhibit the growth of spoilage fungi in processed foods. Scope and Approach: Therefore, this review summarizes the discovery and development of antifungal peptides using lactic acid bacteria fermentation to prevent food spoilage by fungi. The focus of this review will be on the identification of antifungal peptides, potential sources, the possible modes of action and properties of peptides considered to inhibit the growth of spoilage fungi. Key Findings and Conclusions: Antifungal peptides generated by certain lactic acid bacteria strains have a high potential for applications in a broad range of foods. The mechanism of peptides antifungal activity is related to their properties such as low molecular weight, concentration and secondary structure. The antifungal peptides were proposed to be used as bio-preservatives to reduce and/or replace chemical preservatives.

Matched MeSH terms: Drug Discovery
Emerging frontiers of deep eutectic solvents in drug discovery and drug delivery systems

Zainal-Abidin MH, Hayyan M, Ngoh GC, Wong WF, Looi CY

J Control Release, 2019 12 28;316:168-195.
PMID: 31669211 DOI: 10.1016/j.jconrel.2019.09.019

The applications of eutectic systems, including deep eutectic solvents (DESs), in diverse sectors have drawn significant interest from researchers, academicians, engineers, medical scientists, and pharmacists. Eutecticity increases drug dissolution, improves drug penetration, and acts as a synthesis route for drug carriers. To date, DESs have been extensively explored as potential drug delivery systems on account of their unique properties such as tunability and chemical and thermal stability. This review discusses two major topics: first, the application of eutectic mixtures (before and after the introduction of DES) in the field of drug delivery systems, and second, the most promising examples of DES pharmaceutical activity. It also considers future prospects in the medical and biotechnological fields. In addition to the application of DESs in drug delivery systems, they show greatly promising pharmaceutical activities, including anti-fungal, anti-bacterial, anti-viral, and anti-cancer activities. Eutecticity is a valid strategy for overcoming many obstacles inherently associated with either introducing new drugs or enhancing drug delivery systems.

Matched MeSH terms: Drug Discovery/methods
Emerging therapeutic potential of the iridoid molecule, asperuloside: A snapshot of its underlying molecular mechanisms

Chan Y, Ng SW, Xin Tan JZ, Gupta G, Tambuwala MM, Bakshi HA, et al.

Chem Biol Interact, 2019 Nov 28;315:108911.
PMID: 31786185 DOI: 10.1016/j.cbi.2019.108911

Over the years, the attention of researchers in the field of modern drug discovery and development has become further intense on the identification of active compounds from plant sources and traditional remedies, as they exhibit higher therapeutic efficacies and improved toxicological profiles. Among the large diversity of plant extracts that have been discovered and explored for their potential therapeutic benefits, asperuloside, an iridoid glycoside, has been proven to provide promising effects as a therapeutic agent for several diseases. Although, this potent substance exists in several genera, it is primarily found in plants belonging to the genus Eucommia. Recent decades have seen a surge in the research on Asperuloside, making it one of the most studied natural products in the field of medicine and pharmacology. In this review, we have attempted to study the various reported mechanisms of asperuloside that form the basis of its wide spectrum of pharmacological activities.

Matched MeSH terms: Drug Discovery
Efficient differentiation of human ES and iPS cells into cardiomyocytes on biomaterials under xeno-free conditions

Sung TC, Liu CH, Huang WL, Lee YC, Kumar SS, Chang Y, et al.

Biomater Sci, 2019 Oct 28.
PMID: 31656967 DOI: 10.1039/c9bm00817a

Current xeno-free and chemically defined methods for the differentiation of hPSCs (human pluripotent stem cells) into cardiomyocytes are not efficient and are sometimes not reproducible. Therefore, it is necessary to develop reliable and efficient methods for the differentiation of hPSCs into cardiomyocytes for future use in cardiovascular research related to drug discovery, cardiotoxicity screening, and disease modeling. We evaluated two representative differentiation methods that were reported previously, and we further developed original, more efficient methods for the differentiation of hPSCs into cardiomyocytes under xeno-free, chemically defined conditions. The developed protocol successively differentiated hPSCs into cardiomyocytes, approximately 90-97% of which expressed the cardiac marker cTnT, with beating speeds and sarcomere lengths that were similar to those of a healthy adult human heart. The optimal cell culture biomaterials for the cardiac differentiation of hPSCs were also evaluated using extracellular matrix-mimetic material-coated dishes. Synthemax II-coated and Laminin-521-coated dishes were found to be the most effective and efficient biomaterials for the cardiac differentiation of hPSCs according to the observation of hPSC-derived cardiomyocytes with high survival ratios, high beating colony numbers, a similar beating frequency to that of a healthy adult human heart, high purity levels (high cTnT expression) and longer sarcomere lengths similar to those of a healthy adult human heart.

Matched MeSH terms: Drug Discovery
Fulltext In Vivo Anti-Tumor Effects of Citral on 4T1 Breast Cancer Cells via Induction of Apoptosis and Downregulation of Aldehyde Dehydrogenase Activity

Nigjeh SE, Yeap SK, Nordin N, Rahman H, Rosli R

Molecules, 2019 Sep 05;24(18).
PMID: 31492037 DOI: 10.3390/molecules24183241

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among females globally. The tumorigenic activities of cancer cells such as aldehyde dehydrogenase (ALDH) activity and differentiation have contributed to relapse and eventual mortality in breast cancer. Thus, current drug discovery research is focused on targeting breast cancer cells with ALDH activity and their capacity to form secondary tumors. Citral (3,7-dimethyl-2,6-octadienal), from lemon grass (Cymbopogoncitrates), has been previously reported to have a cytotoxic effect on breast cancer cells. Hence, this study was conducted to evaluate the in vivo effect of citral in targeting ALDH activity of breast cancer cells. BALB/c mice were challenged with 4T1 breast cancer cells followed by daily oral feeding of 50 mg/kg citral or distilled water for two weeks. The population of ALDH+ tumor cells and their capacity to form secondary tumors in both untreated and citral treated 4T1 challenged mice were assessed by Aldefluor assay and tumor growth upon cell reimplantation in normal mice, respectively. Citral treatment reduced the size and number of cells with ALDH+ activity of the tumors in 4T1-challenged BALB/c mice. Moreover, citral-treated mice were also observed with smaller tumor size and delayed tumorigenicity after reimplantation of the primary tumor cells into normal mice. These findings support the antitumor effect of citral in targeting ALDH+ cells and tumor recurrence in breast cancer cells.

Matched MeSH terms: Drug Discovery
Recent update on anti-dengue drug discovery

Dighe SN, Ekwudu O, Dua K, Chellappan DK, Katavic PL, Collet TA

Eur J Med Chem, 2019 Aug 15;176:431-455.
PMID: 31128447 DOI: 10.1016/j.ejmech.2019.05.010

Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact on public health, there are no antiviral therapies available, and the only licensed vaccine, Dengvaxia®, has been contraindicated in children below nine years of age. In an effort to combat dengue, several small molecules have entered into human clinical trials. Here, we review anti-DENV molecules and their drug targets that have been published within the past five years (2014-2018). Further, we discuss their probable mechanisms of action and describe a role for classes of clinically approved drugs and also an unclassified class of anti-DENV agents. This review aims to enhance our understanding of novel agents and their cognate targets in furthering innovations in the use of small molecules for dengue drug therapies.

Matched MeSH terms: Drug Discovery

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