scholarly journals Structure-Function Characteristics of SARS-CoV-2 Proteases and Their Potential Inhibitors from Microbial Sources

2021 ◽  
Vol 9 (12) ◽  
pp. 2481
Author(s):  
Rafida Razali ◽  
Haslina Asis ◽  
Cahyo Budiman
Keyword(s):  
Drug Targets ◽  
New Drugs ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Design Strategies ◽  
Viral Proteases ◽  
Bacteria And Fungi ◽  
And Function ◽  
Potential Inhibitors ◽  
Microbial Sources

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is considered the greatest challenge to the global health community of the century as it continues to expand. This has prompted immediate urgency to discover promising drug targets for the treatment of COVID-19. The SARS-CoV-2 viral proteases, 3-chymotrypsin-like protease (3CLpro) and papain-like cysteine protease (PLpro), have become the promising target to study due to their essential functions in spreading the virus by RNA transcription, translation, protein synthesis, processing and modification, virus replication, and infection of the host. As such, understanding of the structure and function of these two proteases is unavoidable as platforms for the development of inhibitors targeting this protein which further arrest the infection and spread of the virus. While the abundance of reports on the screening of natural compounds such as SARS-CoV-2 proteases inhibitors are available, the microorganisms-based compounds (peptides and non-peptides) remain less studied. Indeed, microorganisms-based compounds are also one of the potent antiviral candidates against COVID-19. Microbes, especially bacteria and fungi, are other resources to produce new drugs as well as nucleosides, nucleotides, and nucleic acids. Thus, we have compiled various reported literature in detail on the structures, functions of the SARS-CoV-2 proteases, and potential inhibitors from microbial sources as assistance to other researchers working with COVID-19. The compounds are also compared to HIV protease inhibitors which suggested the microorganisms-based compounds are advantageous as SARS-CoV2 proteases inhibitors. The information should serve as a platform for further development of COVID-19 drug design strategies.

Proteases as drug targets

2003 ◽  
Vol 70 ◽  
pp. 147-161 ◽  
Author(s):  
Andy J. Docherty ◽  
Tom Crabbe ◽  
James P. O'Connell ◽  
Colin R. Groom
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Targets ◽  
Enzyme Inhibitors ◽  
Proteolytic Enzymes ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
Recent Success ◽  
The Impact

The effective management of AIDS with HIV protease inhibitors, or the use of angiotensin-converting enzyme inhibitors to treat hypertension, indicates that proteases do make good drug targets. On the other hand, matrix metalloproteinase (MMP) inhibitors from several companies have failed in both cancer and rheumatoid arthritis clinical trials. Mindful of the MMP inhibitor experience, this chapter explores how tractable proteases are as drug targets from a chemistry perspective. It examines the recent success of other classes of drug for the treatment of rheumatoid arthritis, and highlights the need to consider where putative targets lie on pathophysiological pathways--regardless of what kind of therapeutic entity would be required to target them. With genome research yielding many possible new drug targets, it explores the likelihood of discovering proteolytic enzymes that are causally responsible for disease processes and that might therefore make better targets, especially if they lead to the development of drugs that can be administered orally. It also considers the impact that biologics are having on drug discovery, and in particular whether biologically derived therapeutics such as antibodies are likely to significantly alter the way we view proteases as targets and the methods used to discover therapeutic inhibitors.

Antimalarials: Review of Plasmepsins as Drug Targets and HIV Protease Inhibitors Interactions

2019 ◽  
Vol 18 (23) ◽  
pp. 2022-2028 ◽  
Author(s):  
Whelton A. Miller III ◽  
Joshua Teye ◽  
Angela O. Achieng ◽  
Reagan M. Mogire ◽  
Hoseah Akala ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Drug Targets ◽  
Eastern Mediterranean ◽  
Sub Saharan Africa ◽  
Hiv Protease ◽  
World Health ◽  
Health Concern ◽  
Hiv Protease Inhibitors ◽  
Aspartic Proteases ◽  
Health Organization

Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.

scholarly journals Potential COVID-19 Protease Inhibitors: Repurposing FDAapproved Drugs

2020 ◽  
Author(s):  
Valentina Kouznetsova ◽  
David Huang ◽  
Igor F. Tsigelny
Keyword(s):  
Protease Inhibitors ◽  
Binding Pocket ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Free Energies ◽  
Inhibitor Binding ◽  
Approved Drugs ◽  
Docking Interaction ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

Using as a template the crystal structure of COVID-19 protease, we developed a pharmacophore of functional centers of the protease inhibitor-binding pocket. Then we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of COVID-19 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin—the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.<br><br>

scholarly journals Identification of Potential Inhibitors of SARS-CoV-2 Main Protease via a Rapid In-Silico Drug Repurposing Approach

2020 ◽  
Author(s):  
Cesar Mendoza-Martinez ◽  
Alejandro Rodriguez-Lezama
Keyword(s):  
In Silico ◽  
Antiviral Agents ◽  
Drug Repurposing ◽  
Binding Mode ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Binding Modes ◽  
Data Set ◽  
Main Protease ◽  
Potential Inhibitors

An in-silico drug repurposing study was carried out to search for potential COVID-19 antiviral agents. A dataset of 1615 FDA-approved drugs was docked in the active site of SARS CoV-2 Main protease. A subset of the top scoring hit compounds was subjected to follow-up molecular dynamics simulations to further characterise the predicted binding modes. The main findings are that the drugs Aliskiren, Capreomycin, Isovuconazonium, emerge as novel potential inhibitors. We also observed that Ceftolozane, Cobicistat, Carfilzomib and Saquinavir are well-ranked by our protocol, in agreement with other recent in silico drug repurposing studies, however MD simulations shows only potential for the three first, as Saquinavir exhibited an unstable binding mode. As many HIV-protease inhibitors has been reported as active and not active, Atazanavir and Lopinavir were included in the data set in order to rationalize the findings. In addition, our protocol ranked favourably Dronedarone suggesting that this recently reported SARS-CoV-2 inhibitor targets SARS-CoV-2 Main protease.

scholarly journals Identification of Potential Inhibitors of SARS-CoV-2 Main Protease via a Rapid In-Silico Drug Repurposing Approach

2020 ◽  
Author(s):  
Cesar Mendoza-Martinez ◽  
Alejandro Rodriguez-Lezama
Keyword(s):  
In Silico ◽  
Antiviral Agents ◽  
Drug Repurposing ◽  
Binding Mode ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Binding Modes ◽  
Data Set ◽  
Main Protease ◽  
Potential Inhibitors

An in-silico drug repurposing study was carried out to search for potential COVID-19 antiviral agents. A dataset of 1615 FDA-approved drugs was docked in the active site of SARS CoV-2 Main protease. A subset of the top scoring hit compounds was subjected to follow-up molecular dynamics simulations to further characterise the predicted binding modes. The main findings are that the drugs Aliskiren, Capreomycin, Isovuconazonium, emerge as novel potential inhibitors. We also observed that Ceftolozane, Cobicistat, Carfilzomib and Saquinavir are well-ranked by our protocol, in agreement with other recent in silico drug repurposing studies, however MD simulations shows only potential for the three first, as Saquinavir exhibited an unstable binding mode. As many HIV-protease inhibitors has been reported as active and not active, Atazanavir and Lopinavir were included in the data set in order to rationalize the findings. In addition, our protocol ranked favourably Dronedarone suggesting that this recently reported SARS-CoV-2 inhibitor targets SARS-CoV-2 Main protease.

scholarly journals Potential COVID-19 Protease Inhibitors: Repurposing FDAapproved Drugs

2020 ◽  
Author(s):  
Valentina Kouznetsova ◽  
David Huang ◽  
Igor F. Tsigelny
Keyword(s):  
Protease Inhibitors ◽  
Binding Pocket ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Free Energies ◽  
Inhibitor Binding ◽  
Approved Drugs ◽  
Docking Interaction ◽  
Potential Inhibitors ◽  
Fda Approved Drugs

Using as a template the crystal structure of COVID-19 protease, we developed a pharmacophore of functional centers of the protease inhibitor-binding pocket. Then we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of COVID-19 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin—the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.<br><br>

Natural Products for the Treatment of Neurodegenerative Diseases

2020 ◽  
Vol 27 (34) ◽  
pp. 5790-5828 ◽  
Author(s):  
Ze Wang ◽  
Chunyang He ◽  
Jing-Shan Shi
Keyword(s):  
Nervous System ◽  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Neuroprotective Effect ◽  
Rapid Development ◽  
New Drugs ◽  
Progressive Degeneration ◽  
Cord Injury ◽  
The Central Nervous System ◽  
And Function

Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. Alzheimer&#039;s Disease (AD), Parkinson&#039;s Disease (PD) and Spinal Cord Injury (SCI) are the common neurodegenerative diseases, which typically occur in people over the age of 60. With the rapid development of an aged society, over 60 million people worldwide are suffering from these uncurable diseases. Therefore, the search for new drugs and therapeutic methods has become an increasingly important research topic. Natural products especially those from the Traditional Chinese Medicines (TCMs), are the most important sources of drugs, and have received extensive interest among pharmacist. In this review, in order to facilitate further chemical modification of those useful natural products by pharmacists, we will bring together recent studies in single natural compound from TCMs with neuroprotective effect.

Molecular characterization of SARS-CoV-2

2020 ◽  
Vol 20 ◽  
Author(s):  
Miribane Dërmaku-Sopjani ◽  
Mentor Sopjani
Keyword(s):  
Public Health ◽  
Drug Targets ◽  
Virus Genome ◽  
Health Crisis ◽  
Public Health Crisis ◽  
Therapeutic Drugs ◽  
New Public Health ◽  
New Public ◽  
And Function

Abstract:: The coronavirus disease 2019 (COVID-19) is currently a new public health crisis threatening the world. This pandemic disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus has been reported to be originated in bats and by yet unknown intermediary animals were transmitted to humans in China 2019. The SARSCoV- 2 spreads faster than its two ancestors the SARS-CoV and Middle East respiratory syndrome coronavirus (MERSCoV) but has reduced fatality. At present, the SARS-CoV-2 has caused about a 1.16 million of deaths with more than 43.4 million confirmed cases worldwide, resulting in a serious threat to public health globally with yet uncertain impact. The disease is transmitted by inhalation or direct contact with an infected person. The incubation period ranges from 1 to 14 days. COVID-19 is accompanied by various symptoms, including cough, fatigue. In most people the disease is mild, but in some other people, such as in elderly and people with chronic diseases, it may progress from pneumonia to a multi-organ dysfunction. Many people are reported asymptomatic. The virus genome is sequenced, but new variants are reported. Numerous biochemical aspects of its structure and function are revealed. To date, no clinically approved vaccines and/or specific therapeutic drugs are available to prevent or treat the COVID-19. However, there are reported intensive researches on the SARSCoV- 2 to potentially identify vaccines and/or drug targets, which may help to overcome the disease. In this review, we discuss recent advances in understanding the molecular structure of SARS-CoV-2 and its biochemical characteristics.

Determining and Overcoming Resistance to HIV Protease Inhibitors

2004 ◽  
Vol 4 (2) ◽  
pp. 137-152 ◽  
Author(s):  
Jana Prejdova ◽  
Milan Soucek ◽  
Jan Konvalinka
Keyword(s):  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

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