Displaying publications 1 - 20 of 43 in total

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  1. Chan LC, Mat Yassim AS, Ahmad Fuaad AAH, Leow TC, Sabri S, Radin Yahaya RS, et al.
    Sci Rep, 2023 Nov 17;13(1):20178.
    PMID: 37978223 DOI: 10.1038/s41598-023-47511-z
    COVID-19 results from SARS-CoV-2, which mutates frequently, challenging current treatments. Therefore, it is critical to develop new therapeutic drugs against this disease. This study explores the interaction between SARS-CoV-2 3CLpro and RetroMAD1, a well-characterized coronavirus protein and potential drug target, using in-silico methods. The analysis through the HDOCK server showed stable complex formation with a binding energy of -12.3, the lowest among reference drugs. The RetroMAD1-3CLpro complex underwent a 100 ns molecular dynamics simulation (MDS) in an explicit solvation system, generating various trajectories, including RMSD, RMSF, hydrogen bonding, radius of gyration, and ligand binding energy. MDS results confirmed intact interactions within the RetroMAD1-3CLpro complex during simulations. In vitro experiments validated RetroMAD1's ability to inhibit 3CLpro enzyme activity and prevent SARS-CoV-2 infection in human bronchial cells. RetroMAD1 exhibited antiviral efficacy comparable to Remdesivir without cytotoxicity at effective concentrations. These results suggest RetroMAD1 as a potential drug candidate against SARS-CoV-2, warranting further in vivo and clinical studies to assess its efficiency.
    Matched MeSH terms: Protease Inhibitors/pharmacology
  2. Riaz F, Hossain MS, Roney M, Ali Y, Qureshi S, Muhammad R, et al.
    J Biomol Struct Dyn, 2023 Nov;41(19):9756-9769.
    PMID: 36399018 DOI: 10.1080/07391102.2022.2146200
    Antimicrobial drug resistance (AMR) is a severe global threat to public health. The increasing emergence of drug-resistant bacteria requires the discovery of novel antibacterial agents. Quinoline derivatives have previously been reported to exhibit antimalarial, antiviral, antitumor, antiulcer, antioxidant and, most interestingly, antibacterial properties. In this study, we evaluated the binding affinity of three newly designed hydroxyquinolines derived from sulfanilamide (1), 4-amino benzoic acid (2) and sulfanilic acid (3) towards five bacterial protein targets (PDB ID: 1JIJ, 3VOB, 1ZI0, 6F86, 4CJN). The three derivatives were designed considering the amino acid residues identified at the active site of each protein involved in the binding of each co-crystallized ligand and drug-likeness properties. The ligands displayed binding energy values with the target proteins ranging from -2.17 to -8.45 kcal/mol. Compounds (1) and (3) showed the best binding scores towards 1ZI0/3VOB and 1JIJ/4CJN, respectively, which may serve as new antibiotic scaffolds. Our in silico results suggest that sulfanilamide (1) or sulfanilic acid (3) hydroxyquinoline derivatives have the potential to be developed as bacterial inhibitors, particularly MRSA inhibitors. But before that, it must go through the proper preclinical and clinical trials for further scientific validation. Further experimental studies are warranted to explore the antibacterial potential of these compounds through preclinical and clinical studies.Communicated by Ramaswamy H. Sarma.
    Matched MeSH terms: Protease Inhibitors
  3. Ferdous N, Reza MN, Hossain MU, Mahmud S, Napis S, Chowdhury K, et al.
    PLoS One, 2023;18(6):e0287179.
    PMID: 37352252 DOI: 10.1371/journal.pone.0287179
    The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged in 2019 and still requiring treatments with fast clinical translatability. Frequent occurrence of mutations in spike glycoprotein of SARS-CoV-2 led the consideration of an alternative therapeutic target to combat the ongoing pandemic. The main protease (Mpro) is such an attractive drug target due to its importance in maturating several polyproteins during the replication process. In the present study, we used a classification structure-activity relationship (CSAR) model to find substructures that leads to to anti-Mpro activities among 758 non-redundant compounds. A set of 12 fingerprints were used to describe Mpro inhibitors, and the random forest approach was used to build prediction models from 100 distinct data splits. The data set's modelability (MODI index) was found to be robust, with a value of 0.79 above the 0.65 threshold. The accuracy (89%), sensitivity (89%), specificity (73%), and Matthews correlation coefficient (79%) used to calculate the prediction performance, was also found to be statistically robust. An extensive analysis of the top significant descriptors unveiled the significance of methyl side chains, aromatic ring and halogen groups for Mpro inhibition. Finally, the predictive model is made publicly accessible as a web-app named Mpropred in order to allow users to predict the bioactivity of compounds against SARS-CoV-2 Mpro. Later, CMNPD, a marine compound database was screened by our app to predict bioactivity of all the compounds and results revealed significant correlation with their binding affinity to Mpro. Molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) analysis showed improved properties of the complexes. Thus, the knowledge and web-app shown herein can be used to develop more effective and specific inhibitors against the SARS-CoV-2 Mpro. The web-app can be accessed from https://share.streamlit.io/nadimfrds/mpropred/Mpropred_app.py.
    Matched MeSH terms: Protease Inhibitors/pharmacology
  4. Choe J, Har Yong P, Xiang Ng Z
    Chem Biodivers, 2022 Nov;19(11):e202200655.
    PMID: 36125969 DOI: 10.1002/cbdv.202200655
    Selected traditional medicinal plants exhibit therapeutic effects in coronavirus disease (Covid-19) patients. This review aims to identify the phytochemicals from five traditional medicinal plants (Glycyrrhiza glabra, Nigella sativa, Curcuma longa, Tinospora cordifolia and Withania somnifera) with high potential in modulating the main protease (Mpro) activity and cytokine storm in Covid-19 infection. The Mpro binding affinity of 13 plant phytochemicals were in the following order: Withanoside II>withanoside IV>withaferin A>α-hederin>withanoside V>sitoindoside IX>glabridin>liquiritigenin, nigellidine>curcumin>glycyrrhizin>tinocordiside>berberine. Among these phytochemicals, glycyrrhizin, withaferin A, curcumin, nigellidine and cordifolioside A suppressed SARS-CoV-2 replication and showed stronger anti-inflammatory activities than standard Covid-19 drugs. Both preclinical and clinical evidences supported the development of plant bioactive compounds as Mpro inhibitors.
    Matched MeSH terms: Protease Inhibitors/chemistry
  5. Peksheva O, Kuzovatova E, Parfenova O, Zaytseva N
    Viruses, 2022 Aug 27;14(9).
    PMID: 36146704 DOI: 10.3390/v14091898
    The increasing number of HIV-infected people who are receiving ART, including those with low adherence, is causing the spread of HIV drug resistance (DR). A total of 1396 plasma samples obtained from treatment-experienced patients from the Volga federal district (VFD), Russia, were examined to investigate HIV DR occurrence. The time periods 2008−2015 and 2016−2019 were compared. Fragmentary Sanger sequencing was employed to identify HIV resistance to reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) using an ABI 3500XL genetic analyzer, a ViroSeq™ HIV-1 genotyping system (Alameda, CA, USA) and AmpliSense HIV-Resist-Seq reagent kits (Moscow, Russia). In 2016−2019, HIV DR was detected significantly more often than in 2008−2015 (p < 0.01). Mutations to RTIs retained leading positions in the structure of DR. Frequencies of resistance mutations to nucleoside and non-nucleoside RTIs (NRTIs and NNRTIs) in the spectra of detected mutations show no significant differences. Resistance to NRTIs after 2016 began to be registered more often as a part of multidrug resistance (MDR), as opposed to resistance to a single class of antiretrovirals. The frequency of DR mutations to PIs was low, both before and after 2016 (7.9% and 6.1% in the spectrum, respectively, p > 0.05). MDR registration rate became significantly higher from 2008 to 2019 (17.1% to 72.7% of patients, respectively, p < 0.01). M184V was the dominant replacement in all the years of study. A significant increase in the frequency of K65R replacement was revealed. The prevalence of integrase strand transfer inhibitor (INSTI) resistance mutations remains to be investigated.
    Matched MeSH terms: Protease Inhibitors/pharmacology
  6. Selvaraj BA, Mariatulqabtiah AR, Ho KL, Ng CL, Yong CY, Tan WS
    Int J Mol Sci, 2021 Aug 13;22(16).
    PMID: 34445426 DOI: 10.3390/ijms22168725
    The causative agent of white tail disease (WTD) in the giant freshwater prawn is Macrobrachium rosenbergii nodavirus (MrNV). The recombinant capsid protein (CP) of MrNV was previously expressed in Escherichia coli, and it self-assembled into icosahedral virus-like particles (VLPs) with a diameter of approximately 30 nm. Extensive studies on the MrNV CP VLPs have attracted widespread attention in their potential applications as biological nano-containers for targeted drug delivery and antigen display scaffolds for vaccine developments. Despite their advantageous features, the recombinant MrNV CP VLPs produced in E. coli are seriously affected by protease degradations, which significantly affect the yield and stability of the VLPs. Therefore, the aim of this study is to enhance the stability of MrNV CP by modulating the protease degradation activity. Edman degradation amino acid sequencing revealed that the proteolytic cleavage occurred at arginine 26 of the MrNV CP. The potential proteases responsible for the degradation were predicted in silico using the Peptidecutter, Expasy. To circumvent proteolysis, specific protease inhibitors (PMSF, AEBSF and E-64) were tested to reduce the degradation rates. Modulation of proteolytic activity demonstrated that a cysteine protease was responsible for the MrNV CP degradation. The addition of E-64, a cysteine protease inhibitor, remarkably improved the yield of MrNV CP by 2.3-fold compared to the control. This innovative approach generates an economical method to improve the scalability of MrNV CP VLPs using individual protease inhibitors, enabling the protein to retain their structural integrity and stability for prominent downstream applications including drug delivery and vaccine development.
    Matched MeSH terms: Protease Inhibitors/pharmacology
  7. Koh HM, Chong PF, Tan JN, Chidambaram SK, Chua HJ
    J Clin Pharm Ther, 2021 Jun;46(3):800-806.
    PMID: 33768612 DOI: 10.1111/jcpt.13356
    WHAT IS KNOWN AND OBJECTIVE: Hydroxychloroquine and protease inhibitors were widely used as off-label treatment options for COVID-19 but the safety data of these drugs among the COVID-19 population are largely lacking. Drug-induced QTc prolongation is a known adverse reaction of hydroxychloroquine, especially during chronic treatment. However, when administered concurrently with potential pro-arrhythmic drugs such as protease inhibitors, the risk of QTc prolongation imposed on these patients is not known. We aim to investigate the incidence of QTc prolongation events and potential factors associated with its occurrence in COVID-19 population.

    METHODS: We included 446 SARS-CoV-2 RT-PCR-positive patients taking at least one treatment drug for COVID-19 within a period of one month (March-April 2020). In addition to COVID-19-related treatment (HCQ/PI), concomitant drugs with risks of QTc prolongation were considered. We defined QTc prolongation as QTc interval of ≥470 ms in postpubertal males, and ≥480 ms in postpubertal females.

    RESULTS AND DISCUSSION: QTc prolongation events occurred in 28/446 (6.3%) patients with an incidence rate of 1 case per 100 person-days. A total of 26/28 (93%) patients who had prolonged QTc intervals received at least two pro-QT drugs. Multivariate analysis showed that HCQ and PI combination therapy had five times higher odds of QTc prolongation as compared to HCQ-only therapy after controlling for age, cardiovascular disease, SIRS and the use of concurrent QTc-prolonging agents besides HCQ and/or PI (OR 5.2; 95% CI, 1.11-24.49; p = 0.036). Independent of drug therapy, presence of SIRS resulted in four times higher odds of QTc prolongation (OR 4.3; 95% CI, 1.66-11.06; p = 0.003). In HCQ-PI combination group, having concomitant pro-QT drugs led to four times higher odds of QTc prolongation (OR 3.8; 95% CI, 1.53-9.73; p = 0.004). Four patients who had prolonged QTc intervals died but none were cardiac-related deaths.

    WHAT IS NEW AND CONCLUSION: In our cohort, hydroxychloroquine monotherapy had low potential to increase QTc intervals. However, when given concurrently with protease inhibitors which have possible or conditional risk, the odds of QTc prolongation increased fivefold. Interestingly, independent of drug therapy, the presence of systemic inflammatory response syndrome (SIRS) resulted in four times higher odds of QTc prolongation, leading to the postulation that some QTc events seen in COVID-19 patients may be due to the disease itself. ECG monitoring should be continued for at least a week from the initiation of treatment.

    Matched MeSH terms: Protease Inhibitors/adverse effects*
  8. Sivasothy Y, Liew SY, Othman MA, Abdul Wahab SM, Hariono M, Mohd Nawi MS, et al.
    Trop Biomed, 2021 Jun 01;38(2):79-84.
    PMID: 33973577 DOI: 10.47665/tb.38.2.044
    The NS2B/NS3 protease is crucial for the pathogenesis of the DENV. Therefore, the inhibition of this protease is considered to be the key strategy for the development of new antiviral drugs. In the present study, malabaricones C (3) and E (4), acylphenols from the fruits of Myristica cinnamomea King, have been respectively identified as moderate (27.33 ± 5.45 μM) and potent (7.55 ± 1.64 μM) DENV-2 NS2B/NS3 protease inhibitors, thus making this the first report on the DENV-2 NS2B/NS3 protease inhibitory activity of acylphenols. Based on the molecular docking studies, compounds 3 and 4 both have π-π interactions with Tyr161. While compound 3 has hydrogen bonding interactions with Gly151, Gly153 and Tyr161, compound 4 however, forms hydrogen bonds with Ser135, Asp129, Phe130 and Ile86 instead. The results from the present study suggests that malabaricones C (3) and E (4) could be employed as lead compounds for the development of new dengue antivirals from natural origin.
    Matched MeSH terms: Protease Inhibitors
  9. Ross J, Jiamsakul A, Kumarasamy N, Azwa I, Merati TP, Do CD, et al.
    HIV Med, 2021 Mar;22(3):201-211.
    PMID: 33151020 DOI: 10.1111/hiv.13006
    OBJECTIVES: To assess second-line antiretroviral therapy (ART) virological failure and HIV drug resistance-associated mutations (RAMs), in support of third-line regimen planning in Asia.

    METHODS: Adults > 18 years of age on second-line ART for ≥ 6 months were eligible. Cross-sectional data on HIV viral load (VL) and genotypic resistance testing were collected or testing was conducted between July 2015 and May 2017 at 12 Asia-Pacific sites. Virological failure (VF) was defined as VL > 1000 copies/mL with a second VL > 1000 copies/mL within 3-6 months. FASTA files were submitted to Stanford University HIV Drug Resistance Database and RAMs were compared against the IAS-USA 2019 mutations list. VF risk factors were analysed using logistic regression.

    RESULTS: Of 1378 patients, 74% were male and 70% acquired HIV through heterosexual exposure. At second-line switch, median [interquartile range (IQR)] age was 37 (32-42) years and median (IQR) CD4 count was 103 (43.5-229.5) cells/µL; 93% received regimens with boosted protease inhibitors (PIs). Median duration on second line was 3 years. Among 101 patients (7%) with VF, CD4 count > 200 cells/µL at switch [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.17-0.77 vs. CD4 ≤ 50) and HIV exposure through male-male sex (OR = 0.32, 95% CI: 0.17-0.64 vs. heterosexual) or injecting drug use (OR = 0.24, 95% CI: 0.12-0.49) were associated with reduced VF. Of 41 (41%) patients with resistance data, 80% had at least one RAM to nonnucleoside reverse transcriptase inhibitors (NNRTIs), 63% to NRTIs, and 35% to PIs. Of those with PI RAMs, 71% had two or more.

    CONCLUSIONS: There were low proportions with VF and significant RAMs in our cohort, reflecting the durability of current second-line regimens.

    Matched MeSH terms: Protease Inhibitors
  10. Bourgi R, Daood U, Bijle MN, Fawzy A, Ghaleb M, Hardan L
    Polymers (Basel), 2021 Feb 26;13(5).
    PMID: 33652596 DOI: 10.3390/polym13050704
    Enzymatic biodegradation of demineralized collagen fibrils could lead to the reduction of resin-dentin bond strength. Therefore, methods that provide protection to collagen fibrils appear to be a pragmatic solution to improve bond strength. Thus, the study's aim was to investigate the effect of ribose (RB) on demineralized resin-dentin specimens in a modified universal adhesive. Dentin specimens were obtained, standardized and then bonded in vitro with a commercial multi-mode adhesive modified with 0, 0.5%, 1%, and 2% RB, restored with resin composite, and tested for micro-tensile bond strength (µTBS) after storage for 24 h in artificial saliva. Scanning electron microscopy (SEM) was performed to analyze resin-dentin interface. Contact angles were analyzed using a contact angle analyzer. Depth of penetration of adhesives and nanoleakage were assessed using micro-Raman spectroscopy and silver tracing. Molecular docking studies were carried out using Schrodinger small-molecule drug discovery suite 2019-4. Matrix metalloproteinases-2 (MMP-2) and cathepsin-K activities in RB-treated specimens were quantified using enzyme-linked immunosorbent assay (ELISA). The significance level was set at α = 0.05 for all statistical analyses. Incorporation of RB at 1% or 2% is of significant potential (p < 0.05) as it can be associated with improved wettability on dentin surfaces (0.5% had the lowest contact angle) as well as appreciable hybrid layer quality, and higher resin penetration. Improvement of the adhesive bond strength was shown when adding RB at 1% concentration to universal adhesive (p < 0.05). Modified adhesive increased the resistance of collagen degradation by inhibiting MMP-2 and cathepsin-K. A higher RB concentration was associated with improved results (p < 0.01). D-ribose showed favorable negative binding to collagen. In conclusion, universal adhesive using 1% or 2% RB helped in maintaining dentin collagen scaffold and proved to be successful in improving wettability, protease inhibition, and stability of demineralized dentin substrates. A more favorable substrate is created which, in turn, leads to a more stable dentin-adhesive bond. This could lead to more advantageous outcomes in a clinical scenario where a stable bond may result in longevity of the dental restoration.
    Matched MeSH terms: Protease Inhibitors
  11. Lim SK, Othman R, Yusof R, Heh CH
    Chem Biol Drug Des, 2021 01;97(1):28-40.
    PMID: 32657543 DOI: 10.1111/cbdd.13756
    Structure-based virtual screening (SBVS) has served as a popular strategy for rational drug discovery. In this study, we aimed to discover novel benzopyran-based inhibitors that targeted the NS3 enzymes (NS3/4A protease and NS3 helicase) of HCV G3 using a combination of in silico and in vitro approaches. With the aid of SBVS, six novel compounds were discovered to inhibit HCV G3 NS3/4A protease and two phytochemicals (ellagic acid and myricetin) were identified as dual-target inhibitors that inhibited both NS3/4A protease and NS3 helicase in vitro (IC50  = 40.37 ± 5.47 nm and 6.58 ± 0.99 µm, respectively). Inhibitory activities against the replication of HCV G3 replicons were further assessed in a cell-based system with four compounds showed dose-dependent inhibition. Compound P8 was determined to be the most potent compound from the cell-based assay with an EC50 of 19.05 µm. The dual-target inhibitor, ellagic acid, was determined as the second most potent (EC50  = 32.37 µm) and the most selective in its inhibitory activity against the replication of HCV replicons, without severely affecting the viability of the host cells (selectivity index > 6.18).
    Matched MeSH terms: Protease Inhibitors/metabolism; Protease Inhibitors/pharmacology; Protease Inhibitors/chemistry*
  12. Sakharkar MK, Dhillon SK, Mazumder M, Yang J
    Genes Cancer, 2021;12:12-24.
    PMID: 33884102 DOI: 10.18632/genesandcancer.210
    Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal type of cancer. In this study, we undertook a pairwise comparison of gene expression pattern between tumor tissue and its matching adjacent normal tissue for 45 PDAC patients and identified 22 upregulated and 32 downregulated genes. PPI network revealed that fibronectin 1 and serpin peptidase inhibitor B5 were the most interconnected upregulated-nodes. Virtual screening identified bleomycin exhibited reasonably strong binding to both proteins. Effect of bleomycin on cell viability was examined against two PDAC cell lines, AsPC-1 and MIA PaCa-2. AsPC-1 did not respond to bleomycin, however, MIA PaCa-2 responded to bleomycin with an IC50 of 2.6 μM. This implicates that bleomycin could be repurposed for the treatment of PDAC, especially in combination with other chemotherapy agents. In vivo mouse xenograft studies and patient clinical trials are warranted to understand the functional mechanism of bleomycin towards PDAC and optimize its therapeutic efficacy. Furthermore, we will evaluate the antitumor activity of the other identified drugs in our future studies.
    Matched MeSH terms: Protease Inhibitors
  13. 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: Protease Inhibitors/therapeutic use*
  14. Villagracia AR, Ong HL, Lagua FM, Alea G
    Heliyon, 2020 Jun;6(6):e04239.
    PMID: 32613118 DOI: 10.1016/j.heliyon.2020.e04239
    Conventional drugs used to treat Tuberculosis (TB) are becoming ineffective due to the occurrence of multiple drug resistant strains of tuberculosis (TB). This has made the TB disease a a serious global health dilemma. Hence, there is desperate necessity for the advancement of new drugs. In this work, the chemical reactivity and bioactivity of several analogs ofpyrazinamide (PZA) were investigated. PZA is one of the first-line of drugs used to treat tuberculosis and is a key contributor to shortening the treatment time for the disease. Chemical reactivity descriptors of pyrazinamide (PZA) and its analogs of acetylsalicyclic acid and salicyclic acid were investigated using conceptual density functional theory in water as a solvent at the MN12SX/Def2TZVP level of theory. Results have shown that all PZA analogs have improved their global and local reactivity indeces as compared to pyrazinamide based on its electronegativity, electrodonating power, electroaccepting power, eletrophilicity, global hardness and dual descriptor condensed fukui indexes. Moreover, their pKa values are slightly higher than PZA. In terms of its drug-likeness, all PZA analogs passed the Lipinski's Rule of Five criteria. Furthermore, their bioactivity scores are significantly better than pyrazinamide indicating good reaction to G-Protein Coupled Receptor (GPCR) ligands, kinase inhibitors, ion channel modulators, nuclear receptor ligands, protease inhibitors and other enzyme targets. Overall, the PZA analogs are found to be promising anti-tuberculosis drugs. Based on global and local reactivity descriptors, pKa and bioactivity scores, PZA analog of 5-n-Octanoylsalicylic acid is the most reactive among the PZA analogs tested.
    Matched MeSH terms: Protease Inhibitors
  15. Abdusalam AAA, Murugaiyah V
    Front Mol Biosci, 2020;7:603037.
    PMID: 33392261 DOI: 10.3389/fmolb.2020.603037
    The rapid outbreak of Coronavirus Disease 2019 (COVID-19) that was first identified in Wuhan, China is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 3CL protease (3CLpro) is the main protease of the SARS-CoV-2, which is responsible for the viral replication and therefore considered as an attractive drug target since to date there is no specific and effective vaccine available against this virus. In this paper, we reported molecular docking-based virtual screening (VS) of 2000 compounds obtained from the ZINC database and 10 FDA-approved (antiviral and anti-malaria) on 3CLpro using AutoDock Vina to find potential inhibitors. The screening results showed that the top four compounds, namely ZINC32960814, ZINC12006217, ZINC03231196, and ZINC33173588 exhibited high affinity at the 3CLpro binding pocket. Their free energy of binding (FEB) were -12.3, -11.9, -11.7, and -11.2 kcal/mol while AutoDock Vina scores were -12.61, -12.32, -12.01, and -11.92 kcal/mol, respectively. These results were better than the co-crystallized ligand N3, whereby its FEB was -7.5 kcal/mol and FDA-approved drugs. Different but stable interactions were obtained between the four identified compounds with the catalytic dyad residues of the 3CLpro. In conclusion, novel 3CLpro inhibitors from the ZINC database were successfully identified using VS and molecular docking approach, fulfilling the Lipinski rule of five, and having low FEB and functional molecular interactions with the target protein. The findings suggests that the identified compounds may serve as potential leads that act as COVID-19 3CLpro inhibitors, worthy for further evaluation and development.
    Matched MeSH terms: Protease Inhibitors
  16. Teoh SL, Lim YH, Lai NM, Lee SWH
    Front Microbiol, 2020;11:1857.
    PMID: 32849448 DOI: 10.3389/fmicb.2020.01857
    The outbreak of a novel coronavirus (SARS-CoV-2) in Wuhan, China in December 2019 has now become a pandemic with no approved therapeutic agent. At the moment, the genomic structure, characteristics, and pathogenic mechanisms of SARS-CoV-2 have been reported. Based upon this information, several drugs including the directly acting antivirals have been proposed to treat people with coronavirus disease 2019 (COVID-19). This rapid review aims to describe the directly acting antivirals that have been examined for use in the management of COVID-19. Searches were conducted in three electronic databases, supplemented with a search on arXiv, bioRxiv, medRxiv, ChinaXiv, ClinicalTrials.gov, and Chinese Clinical Trial Registry for studies examining the use of antivirals in COVID-19 to identify for case reports, case series, observational studies, and randomized controlled studies describing the use of antivirals in COVID-19. Data were extracted independently and presented narratively. A total of 98 studies were included, comprising of 38 published studies and 60 registered clinical trials. These drugs include the broad spectrum antivirals such as umifenovir, protease inhibitors such as lopinavir/ritonavir as well as the RNA-dependent RNA polymerase inhibitors, remdesivir, and favipiravir. Other drugs that have been used include the nucleosidase inhibitors and polymerase acidic endonuclease inhibitors which are currently approved for prevention of influenza infections. While some of the drugs appear promising in small case series and reports, more clinical trials currently in progress are required to provide higher quality evidence.
    Matched MeSH terms: Protease Inhibitors
  17. Hariono M, Choi SB, Roslim RF, Nawi MS, Tan ML, Kamarulzaman EE, et al.
    PLoS One, 2019;14(1):e0210869.
    PMID: 30677071 DOI: 10.1371/journal.pone.0210869
    Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.
    Matched MeSH terms: Protease Inhibitors/chemical synthesis; Protease Inhibitors/pharmacology*; Protease Inhibitors/chemistry*
  18. Bahari MNA, Sakeh NM, Abdullah SNA, Ramli RR, Kadkhodaei S
    BMC Plant Biol, 2018 Dec 29;18(1):377.
    PMID: 30594134 DOI: 10.1186/s12870-018-1594-9
    BACKGROUND: Basal stem rot (BSR) caused by hemibiotroph Ganoderma boninense is a devastating disease resulting in a major loss to the oil palm industry. Since there is no physical symptom in oil palm at the early stage of G. boninense infection, characterisation of molecular defense responses in oil palm during early interaction with the fungus is of the utmost importance. Oil palm (Elaeis guineensis) seedlings were artificially infected with G. boninense inoculums and root samples were obtained following a time-course of 0, 3, 7, and 11 days-post-inoculation (d.p.i) for RNA sequencing (RNA-seq) and identification of differentially expressed genes (DEGs).

    RESULTS: The host counter-attack was evidenced based on fungal hyphae and Ganoderma DNA observed at 3 d.p.i which became significantly reduced at 7 and 11 d.p.i. DEGs revealed upregulation of multifaceted defense related genes such as PR-protein (EgPR-1), protease inhibitor (EgBGIA), PRR protein (EgLYK3) chitinase (EgCht) and expansin (EgEXPB18) at 3 d.p.i and 7 d.p.i which dropped at 11 d.p.i. Later stage involved highly expressed transcription factors EgERF113 and EgMYC2 as potential regulators of necrotrophic defense at 11 d.p.i. The reactive oxygen species (ROS) elicitor: peroxidase (EgPER) and NADPH oxidase (EgRBOH) were upregulated and maintained throughout the treatment period. Growth and nutrient distribution were probably compromised through suppression of auxin signalling and iron uptake genes.

    CONCLUSIONS: Based on the analysis of oil palm gene expression, it was deduced that the biotrophic phase of Ganoderma had possibly occurred at the early phase (3 until 7 d.p.i) before being challenged by the fungus via switching its lifestyle into the necrotrophic phase at later stage (11 d.p.i) and finally succumbed the host. Together, the findings suggest the dynamic defense process in oil palm and potential candidates that can serve as phase-specific biomarkers at the early stages of oil palm-G. boninense interaction.

    Matched MeSH terms: Protease Inhibitors
  19. Abduraman MA, Hariono M, Yusof R, Rahman NA, Wahab HA, Tan ML
    Heliyon, 2018 Dec;4(12):e01023.
    PMID: 30560214 DOI: 10.1016/j.heliyon.2018.e01023
    Background: Dengue infection is an endemic infectious disease and it can lead to dengue fever, dengue hemorrhagic fever, and/or dengue shock syndromes. Dengue NS2B/NS3 protease complex is essential for viral replication and is a primary target for anti-dengue drug development. In this study, a NS2B/NS3 protease inhibition assay was developed using AlphaScreen® beads and was used to screen compounds for their protease inhibition activities.

    Methods: The assay system utilized a known NS2B/NS3 peptide substrate, a recombinant of NS2B/NS3 protease with proprietary StrepTactin® donor and nickel chelate acceptor beads in 384-well format.

    Results: The optimized assay to screen for NS2B/NS3 protease inhibitors was demonstrated to be potentially useful with reasonable z' factor, coefficient variance and signal to background ratio. However, screening of synthesized thioguanine derivatives using the optimized AlphaScreen® assay revealed weak NS2B/NS3 inhibition activities.

    Conclusion: The AlphaScreen® assay to screen for NS2B/NS3 protease inhibitors is potentially applicable for high throughput screening.

    Matched MeSH terms: Protease Inhibitors
  20. Yeo EH, Goh WL, Chow SC
    Toxicol. Mech. Methods, 2018 Mar;28(3):157-166.
    PMID: 28849708 DOI: 10.1080/15376516.2017.1373882
    The leucine aminopeptidase inhibitor, benzyloxycarbonyl-leucine-chloromethylketone (z-L-CMK), was found to be toxic and readily induce cell death in Jurkat T cells. Dose-response studies show that lower concentration of z-L-CMK induced apoptosis in Jurkat T cells whereas higher concentration causes necrosis. In z-L-CMK-induced apoptosis, both the initiator caspases (-8 and -9) and effector caspases (-3 and -6) were processed to their respective subunits. However, the caspases remained intact in z-L-CMK-induced necrosis. The caspase inhibitor, z-VAD-FMK inhibited z-L-CMK-mediated apoptosis and caspase processing but has no effect on z-L-CMK-induced necrosis in Jurkat T cells. The high mobility group protein B1 (HMGB1) protein was found to be released into the culture medium by the necrotic cells and not the apoptotic cells. These results indicate that the necrotic cell death mediated by z-L-CMK at high concentrations is via classical necrosis rather than secondary necrosis. We also demonstrated that cell death mediated by z-L-CMK was associated with oxidative stress via the depletion of intracellular glutathione (GSH) and increase in reactive oxygen species (ROS), which was blocked by N-acetyl cysteine. Taken together, the results demonstrated that z-L-CMK is toxic to Jurkat T cells and induces apoptosis at low concentrations, while at higher concentrations the cells die of necrosis. The toxic side effects in Jurkat T cells mediated by z-L-CMK are associated with oxidative stress via the depletion of GSH and accumulation of ROS.
    Matched MeSH terms: Protease Inhibitors/toxicity*; Protease Inhibitors/chemistry
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