scholarly journals Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 197 ◽  
Author(s):  
Kyeong-Ok Chang ◽  
Yunjeong Kim ◽  
Scott Lovell ◽  
Athri Rathnayake ◽  
William Groutas
Keyword(s):  
Protease Inhibitors ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Cysteine Proteases ◽  
Life Forms ◽  
Biological Processes ◽  
Macrocyclic Compounds ◽  
Viral Proteases ◽  
Wide Range ◽  
Immunodeficiency Virus

Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense investigation as potential therapeutic targets. A wide range of viruses encode proteases which play an essential role in viral replication and, therefore, constitute attractive targets for the development of antiviral therapeutics. There are numerous examples of successful drug development targeting cellular and viral proteases, including antivirals against human immunodeficiency virus and hepatitis C virus. Most FDA-approved antiviral agents are peptidomimetics and macrocyclic compounds that interact with the active site of a targeted protease. Norovirus proteases are cysteine proteases that contain a chymotrypsin-like fold in their 3D structures. This review focuses on our group’s efforts related to the development of norovirus protease inhibitors as potential anti-norovirus therapeutics. These protease inhibitors are rationally designed transition-state inhibitors encompassing dipeptidyl, tripeptidyl and macrocyclic compounds. Highly effective inhibitors validated in X-ray co-crystallization, enzyme and cell-based assays, as well as an animal model, were generated by launching an optimization campaign utilizing the initial hit compounds. A prodrug approach was also explored to improve the pharmacokinetics (PK) of the identified inhibitors.

scholarly journals Protease Inhibitors as Antiviral Agents

1998 ◽  
Vol 11 (4) ◽  
pp. 614-627 ◽  
Author(s):  
A. K. Patick ◽  
K. E. Potts
Keyword(s):  
Protease Inhibitors ◽  
Viral Infections ◽  
Critical Role ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Structural Proteins ◽  
Viral Protease ◽  
Virus Particles ◽  
Viral Proteases ◽  
Viral Polyprotein

SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

scholarly journals Defense against own arms: staphylococcal cysteine proteases and their inhibitors.

2003 ◽  
Vol 50 (3) ◽  
pp. 715-724 ◽  
Author(s):  
Grzegorz Dubin
Keyword(s):  
Staphylococcus Aureus ◽  
Protease Inhibitors ◽  
Current Knowledge ◽  
Cysteine Proteases ◽  
Infection Process ◽  
Secreted Proteins ◽  
Human Pathogen ◽  
Cysteine Protease Inhibitors ◽  
Wide Range

Staphylococcus aureus is a human pathogen causing a wide range of diseases. Most staphylococcal infections, unlike those caused by other bacteria are not toxigenic and very little is known about their pathogenesis. It has been proposed that a core of secreted proteins common to many infectious strains is responsible for colonization and infection. Among those proteins several proteases are present and over the years many different functions in the infection process have been attributed to them. However, little direct, in vivo data has been presented. Two cysteine proteases, staphopain A (ScpA) and staphopain B (SspB) are important members of this group of enzymes. Recently, two cysteine protease inhibitors, staphostatin A and staphostatin B (ScpB and SspC, respectively) were described in S. aureus shedding new light on the complexity of the processes involving the two proteases. The scope of this review is to summarize current knowledge on the network of staphylococcal cysteine proteases and their inhibitors in view of their possible role as virulence factors.

scholarly journals Role of Plasmodium falciparum Digestive Vacuole Plasmepsins in the Specificity and Antimalarial Mode of Action of Cysteine and Aspartic Protease Inhibitors

2009 ◽  
Vol 53 (12) ◽  
pp. 4968-4978 ◽  
Author(s):  
Pedro A. Moura ◽  
John B. Dame ◽  
David A. Fidock
Keyword(s):  
Plasmodium Falciparum ◽  
Protease Inhibitors ◽  
Mode Of Action ◽  
Antimalarial Drug ◽  
Cysteine Proteases ◽  
Aspartic Protease ◽  
Parasite Line ◽  
Digestive Vacuole ◽  
Aspartic Proteases ◽  
Wide Range

ABSTRACT Hemoglobin (Hb) degradation is essential for the growth of the intraerythrocytic stages of malarial parasites. This process, which occurs inside an acidic digestive vacuole (DV), is thought to involve the action of four aspartic proteases, termed plasmepsins (PMs). These enzymes have received considerable attention as potential antimalarial drug targets. Leveraging the availability of a set of PM-knockout lines generated in Plasmodium falciparum, we report here that a wide range of previously characterized or novel aspartic protease inhibitors exert their antimalarial activities independently of their effect on the DV PMs. We also assayed compounds previously shown to inhibit cysteine proteases residing in the DV. The most striking observation was a ninefold increase in the potency of the calpain inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) against parasites lacking all four DV PMs. Genetic ablation of PM III or PM IV also decreased the level of parasite resistance to the β-hematin binding antimalarial chloroquine. On the basis of the findings of drug susceptibility and isobologram assays, as well as the findings of studies of the inhibition of Hb degradation, morphological analyses, and stage specificity, we conclude that the DV PMs and falcipain cysteine proteases act cooperatively in Hb hydrolysis. We also identify several aspartic protease inhibitors, designed to target DV PMs, which appear to act on alternative targets early in the intraerythrocytic life cycle. These include the potent diphenylurea compound GB-III-32, which was found to be fourfold less potent against a P. falciparum line overexpressing plasmepsin X than against the parental nontransformed parasite line. The identification of the mode of action of these inhibitors will be important for future antimalarial drug discovery efforts focusing on aspartic proteases.

scholarly journals Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM 3100), an inhibitor of infectious cell entry.

1996 ◽  
Vol 40 (3) ◽  
pp. 750-754 ◽  
Author(s):  
R Datema ◽  
L Rabin ◽  
M Hincenbergs ◽  
M B Moreno ◽  
S Warren ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Virus Production ◽  
Significant Inhibition ◽  
Cell Entry ◽  
Immunodeficiency Virus ◽  
Antiviral Chemotherapy

SID 791, a bicyclam inhibiting human immunodeficiency virus (HIV) replication in vitro by blocking virus entry into cells, is an effective inhibitor of virus production and of depletion of human CD4+ T cells in HIV type 1-infected SCID-hu Thy/Liv mice. Steady levels of 100 ng of SID 791 or higher per ml in plasma resulted in statistically significant inhibition of p24 antigen formation. Daily injections of SID 791 caused a dose-dependent decrease in viremia, and this inhibition could be potentiated by coadministration of zidovudine or didanose. The present study suggests that SID 791 alone or in combination with licensed antiviral agents may decrease the virus load in HIV-infected patients and, by extension, that the infectious cell entry step is a valid target for antiviral chemotherapy of HIV disease. The SCID-hu Thy/Liv model in effect provides a rapid means of assessing the potential of compounds with novel modes of antiviral action, as well as the potential of antiviral drug combinations.

Benzothiazole moieties and their derivatives as antimicrobial and antiviral agents: A mini-review

2020 ◽  
Vol 11 (3) ◽  
pp. 3309-3315
Author(s):  
Manahil B Elamin ◽  
Amani Abd Elrazig Salman Abd Elaziz ◽  
Emad Mohamed Abdallah
Keyword(s):  
Scientific Literature ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Pharmaceutical Chemistry ◽  
Heterocyclic Chemistry ◽  
Antimicrobial Drugs ◽  
Benzothiazole Derivatives ◽  
Global Concern ◽  
Pharmaceutical Molecules ◽  
Heterocyclic Moiety

Heterocyclic chemistry has provided an inexhaustible source of pharmaceutical molecules. Heterocyclic compounds such as benzothiazole moieties and its derivatives area substantial class of compounds in pharmaceutical chemistry and exhibited therapeutic capabilities, such as antitumor, anticancer, antioxidant, antidiabetic, antiviral, antimicrobial, antimalarial, anthelmintic and other activities. Besides, some antibiotics such as penicillin and cephalosporin have heterocyclic moiety. The growing prevalence of multi-drug resistant pathogens represents serious global concern,which requires the development of new antimicrobial drugs. Moreover, the emergence of pandemic SARSCoV-2 causing Covid-19 disease and all these health dilemmas urge the scientific community to examine the possible antimicrobial and antiviral capacities of some bioactive benzothiazole derivatives against these severe causative agents.This mini-review highlights some recent scientific literature on different benzothiazole molecules and their derivatives. It turns out that, there are numerous synthesized benzothiazole derivatives which exhibited different mode of actions against microorganisms or viruses and accordingly suggested them as an active candidate in the discovery of new antimicrobial or antiviral agents for clinical development. The recommended bioactive benzothiazole derivatives mentioned in the current study are mainly Schiff bases, azo dyes and metal complexes benzothiazole derivatives; the starting material for most of these derivatives are 2-aminobenzothiazole although careful pharmaceutical studies should be conducted to ensure the safety and efficacy of these bioactive synthesized molecules as an antimicrobial or antiviral drug in the future.

scholarly journals Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome

2021 ◽  
Vol 22 (4) ◽  
pp. 1617
Author(s):  
Jimin Xu ◽  
Judith Berastegui-Cabrera ◽  
Marta Carretero-Ledesma ◽  
Haiying Chen ◽  
Yu Xue ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
Antiviral Drug ◽  
Human Adenovirus ◽  
Yield Reduction ◽  
Respiratory Illnesses ◽  
Molecule Inhibitor ◽  
Wide Range ◽  
Ic50 Values ◽  
Life Threatening ◽  
Salicylamide Derivatives

Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI > 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.

scholarly journals Nitrogen-Based Heterocyclic Compounds: A Promising Class of Antiviral Agents against Chikungunya Virus

Life ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 16
Author(s):  
Andreza C. Santana ◽  
Ronaldo C. Silva Filho ◽  
José C. J. M. D. S. Menezes ◽  
Diego Allonso ◽  
Vinícius R. Campos
Keyword(s):  
Antiviral Activity ◽  
Mechanism Of Action ◽  
Heterocyclic Compounds ◽  
Chikungunya Virus ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Important Class ◽  
Available Nitrogen ◽  
Global Threat ◽  
Present Understanding

Arboviruses, in general, are a global threat due to their morbidity and mortality, which results in an important social and economic impact. Chikungunya virus (CHIKV), one of the most relevant arbovirus currently known, is a re-emergent virus that causes a disease named chikungunya fever, characterized by a severe arthralgia (joint pains) that can persist for several months or years in some individuals. Until now, no vaccine or specific antiviral drug is commercially available. Nitrogen heterocyclic scaffolds are found in medications, such as aristeromycin, favipiravir, fluorouracil, 6-azauridine, thioguanine, pyrimethamine, among others. New families of natural and synthetic nitrogen analogous compounds are reported to have significant anti-CHIKV effects. In the present work, we focus on these nitrogen-based heterocyclic compounds as an important class with CHIKV antiviral activity. We summarize the present understanding on this class of compounds against CHIKV and also present their possible mechanism of action.

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