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Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors

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Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors viruses Review Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors Kyeong-Ok Chang 1,*, Yunjeong Kim 1 , Scott Lovell 2, Athri D. Rathnayake 3 and William C. Groutas 3 1 Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA; [email protected] 2 Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA; [email protected] 3 Department of Chemistry, Wichita State University, Wichita, KS 67260, USA; [email protected] (A.D.R.); [email protected] (W.C.G.) * Correspondence: [email protected]; Tel.: +1-785-532-3849; Fax: +1-785-532-4039 Received: 29 January 2019; Accepted: 22 February 2019; Published: 25 February 2019 Abstract: 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. Keywords: noroviruses; 3C-like protease; protease inhibitors; antiviral drug development 1. Introduction Proteases play an important role in the activation of precursor proteins to mature forms, the recycling of proteins, and other essential functions in the body (vide infra) [1]. They are classified into over 80 families based on evolutionary relationships [1]. The major protease classes based on catalytic types include serine, cysteine, aspartic, threonine, glutamic acid, and metalloproteases [1,2]. Most proteases recognize specific sequences of amino acids in their substrates and cleave the peptide bond between the P1 and P1’ residues (Figure1)[ 3] via nucleophilic attack of the side chain of a cysteine, serine or threonine residue, or a water molecule (aspartic, glutamic acid, and metalloproteases) on the amide carbon of the scissile bond [2]. Viruses 2019, 11, 197; doi:10.3390/v11020197 www.mdpi.com/journal/viruses Viruses 2019, 11, 197 2 of 14 Viruses 2019, 11, x FOR PEER REVIEW 2 of 15 FigureFigure 1. 1. ProteolysisProteolysis of of the the scissile scissile bond bond between between P 1 andand P P11’.’. Standard Standard nomenclature nomenclature P P11…... Pn Pandn and P1’… P1 ’ P...n’ forPn ’amino for amino acid acid residues residues of the of thesubstrates. substrates. S1... S S1n... and Sn andS1’… S 1S’n’... areS nthe’ are corresponding the corresponding binding binding sites onsites the on enzyme the enzyme (per Berger (per Berger and Schechter and Schechter nomenclature nomenclature (3)). (3)). ThereThere are approximately 600 600 proteases (~2% (~2% of of the the genomes) genomes) encoded encoded by by the the human human genome. genome. These are involved in a plethora of important ph physiologicalysiological processes, processes, including including protein protein turnover, turnover, digestion,digestion, blood blood coagulation, wo woundund healing, healing, fertilization, fertilization, cell cell differentiation differentiation and and growth, cell signaling,signaling, the the immune response, and apoptosis.apoptosis. However, However, uncontrolled, uncontrolled, poorly poorly regulated, regulated, or or undesiredundesired proteolysis can leadlead toto variousvarious diseasesdiseases [4[4].]. ExamplesExamples ofof thesethese include:include: (1)1) cancer cancer (metastasis,(metastasis, angiogenesis): angiogenesis): proteasome, proteasome, matrix matrix me metalloproteinasestalloproteinases (MMPs), (MMPs), caspases, caspases, and and furin; furin; 2) neurological(2) neurological diseases diseases (Alzheimer’s (Alzheimer’s disease, disease, Park Parkinson’sinson’s disease, disease, ischemia, ischemia, central central nerve nerve system injury):injury): a a disintegrin disintegrin and and metalloproteinase metalloproteinase domain-containing domain-containing protein protein 10 10(ADAM10), (ADAM10), γ-secretase,γ-secretase, β- secretaseβ-secretase 1, 1,and and MMP-24; MMP-24; 3) (3)inflammation inflammation (arthritis, (arthritis, chronic chronic obstructive obstructive pulmonary pulmonary disease disease (COPD), (COPD), asthma,asthma, Crohn’s Crohn’s disease, inflammatory inflammatory bowel bowel disease, disease, colitis, colitis, diverticulitis, diverticulitis, chronic chronic liver liver disease): disease): MMPs,MMPs, cathepsins, cathepsins, neutrophil neutrophil elastase, elastase, and and ADAM17; ADAM17; 4) (4) blood blood coagulation: coagulation: thrombin, thrombin, factor factor Xa; Xa;5) diabetes:(5) diabetes: dipeptidyl dipeptidyl peptidase peptidase 4 (DPP4); 4 (DPP4); 6) (6) cardiovascular cardiovascular disease disease (atherosclerosis, (atherosclerosis, hypertension, hypertension, cardiomyopathy,cardiomyopathy, congestive heart failure, myocardial infarction, neovascularization and and cardiac remodeling,remodeling, cardiac cardiac fibrosis, fibrosis, aneuri aneurism,sm, ischemia-reperfusion ischemia-reperfusion injury): injury): angiotensin angiotensin converting converting enzyme, enzyme, renin,renin, MMPs, chymase, neprilysin, calpain;calpain; (7)7) osteoporosis: osteoporosis: cathepsin K; and (8)8) autoimmune autoimmune diseases diseases (multiple(multiple sclerosis,sclerosis, lupus, lupus, Guillain-Barre Guillain-Barre syndrome, syndrome, psoriasis): psoriasis): activated activated protein protein C, kallikreins; C, kallikreins; ageing ageing(skin), MMPs,(skin), MMPs, neutrophil neutrophil elastase elastase [1,2]. [1,2]. SinceSince poorly-regulated poorly-regulated proteases proteases themselves themselves can be can detrimental, be detrimental, there are there physiological are physiological protease inhibitorsprotease inhibitorsin the body in which the body help which to maintain help to a maintainprotease–protease a protease–protease inhibitor balance inhibitor by controlling balance by aberrantcontrolling protease aberrant activity protease [5–7]. activity Well-known [5–7]. Well-known physiological physiological protease proteaseinhibitors inhibitors include includethe serpin the superfamily,serpin superfamily, consisting consisting of α of-1-antitrypsin,α-1-antitrypsin, α-1-antichymotrypsin,α-1-antichymotrypsin, C1-i C1-inhibitor,nhibitor, antithrombin, antithrombin, plasminogen activatoractivator inhibitor-1, inhibitor-1, and and neuroserpin neuroserpi [6,n7]. [6,7]. Thus, Thus, natural natural or synthetic or synthetic protease inhibitorsprotease inhibitorshave been have studied been and studied developed and developed for various for pathologicalvarious pathological conditions conditions [4] and [4] there and are there several are severalFDA-approved FDA-approved drugs on drugs the market. on the Currently,market. Curre commerciallyntly, commercially available available synthetic proteasesynthetic inhibitorsprotease inhibitorstargeting targeting host proteases host proteases include include (1) thrombin 1) thromb andin Factor and Factor Xa inhibitors Xa inhibitors for coagulationfor coagulation (such (such as asdabigatran dabigatran and and rivaroxaban); rivaroxaban); (2) 2) angiotensin angiotensin converting converting enzymeenzyme (ACE)(ACE) inhibitorsinhibitors for hypertension (such(such as lisinopril); (3)3) DPP-4 DPP-4 inhibitors inhibitors for for diabetes diabetes (such (such as as sitagliptin); sitagliptin); and (4)4) proteasome proteasome inhibitors inhibitors forfor multiple multiple myeloma myeloma (such as bortezomib) (Figure 2 2).). Viruses 2019, 11, 197 3 of 14 Viruses 2019, 11, x FOR PEER REVIEW 3 of 15 Figure 2. ExamplesFigure 2. Examples of commercially of commercially available available protease protease inhibitors inhibitors and their targets. andtheir Dabigatran targets. and Dabigatran and RivaroxabanRivaroxaban are anti-coagulants; are anti-coagulants; LisinoprilLisinopril is fo isr forhypertension; hypertension; Sitagliptin Sitagliptin is for diabetes; is forand diabetes; and Bortezomib is for multiple myeloma. Bortezomib is for multiple myeloma. 2. Human Immunodeficiency Virus (HIV) Protease Inhibitors 2. Human Immunodeficiency Virus (HIV) Protease Inhibitors Certain viruses also encode viral proteases for successful infection of the hosts. The HIV aspartic Certain virusesand hepatitis also C encode virus (HCV) viral NS3-4A proteases serine forprot successfulease are among infection the well-studied
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