Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine

Hulce, Kaitlin R.; Jaishankar, Priyadarshini; Lee, Gregory M.; Bohn, Markus-Frederik; Connelly, Emily; Wucherer, Kristin; Ongpipattanakul, Chayanid; Volk, Regan F.; Chuo, Shih-Wei; Arkin, Michelle R.; Renslo, Adam R.; Craik, Charles S.

doi:10.1016/j.chembiol.2022.03.007

Cited by 8 publications

(5 citation statements)

References 83 publications

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“…Hulce et al synthesized a series of human herpesvirus (HHV) protease inhibitors that act by covalently binding to a non-catalytic residue [ 110 ]. The HHV protease is a family of structurally conserved serine proteases where the active site is comprised of a non-canonical His-His-Ser catalytic triad.…”

Section: Inhibition Of Viral Proteases Through Allosteric Site Modula...mentioning

confidence: 99%

Recent Advances on Targeting Proteases for Antiviral Development

Borges,

Ferreira,

Silva

2024

Viruses

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Viral proteases are an important target for drug development, since they can modulate vital pathways in viral replication, maturation, assembly and cell entry. With the (re)appearance of several new viruses responsible for causing diseases in humans, like the West Nile virus (WNV) and the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding the mechanisms behind blocking viral protease’s function is pivotal for the development of new antiviral drugs and therapeutical strategies. Apart from directly inhibiting the target protease, usually by targeting its active site, several new pathways have been explored to impair its activity, such as inducing protein aggregation, targeting allosteric sites or by inducing protein degradation by cellular proteasomes, which can be extremely valuable when considering the emerging drug-resistant strains. In this review, we aim to discuss the recent advances on a broad range of viral proteases inhibitors, therapies and molecular approaches for protein inactivation or degradation, giving an insight on different possible strategies against this important class of antiviral target.

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Section: Inhibition Of Viral Proteases Through Allosteric Site Modula...mentioning

confidence: 99%

Recent Advances on Targeting Proteases for Antiviral Development

Borges,

Ferreira,

Silva

2024

Viruses

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“…Since this protease plays a crucial role in viral replication, it emerges as a promising target for drug development. Inhibiting viral proteases involved in polypeptide processing has proven to be an effective strategy for treating other viral infections, such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV) (Bianchi and Pessi 2002;Hulce et al 2022).…”

Section: Introductionmentioning

confidence: 99%

Molecular docking-based virtual screening and computational investigations of biomolecules (curcumin analogs) as potential lead inhibitors for SARS-CoV-2 papain-like protease

Fakih,

Ritmaleni,

Zainul

et al. 2024

PHAR

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In the effort to combat SARS-CoV-2 infection, researchers are currently exploring the repurposing of conventional antiviral drugs, despite their limited efficacy. The SARS-CoV-2 virus encodes a papain-like protease (PLpro), which not only plays a crucial role in viral replication but also cleaves ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins, making it a prime target for the development of new antiviral medications. In this study, we conducted a multi-step in silico screening to identify novel, noncovalent PLpro inhibitors. Curcumin, an antioxidant derived from turmeric rhizomes (Curcuma longa L.), has undergone extensive preclinical investigations and shown significant efficacy against viruses and other ailments in both laboratory and animal studies. However, the pharmacological limitations of curcumin have prompted the synthesis of numerous novel curcumin analogs, necessitating evaluation for their therapeutic potential. The selectivity of the top-scoring compounds was assessed through molecular docking studies and molecular dynamics simulations to determine their binding affinity to PLpro. As a result, we identified 20 potential, selective PLpro inhibitors, from which the top two compounds (THA111 and THHGV6) were selected based on their binding free energy values towards PLpro as estimated by MM-PBSA calculations. These selected candidates demonstrate promising activity against the protein, with binding free energy values ranging from approximately −105 to −108 kJ/mol, and largely adopt a similar binding mode to known noncovalent SARS-CoV-2PLpro inhibitors (GRL0617 = −100.98 kJ/mol). We further propose these two most promising compounds for future in vitro evaluation. The findings for the top potential PLpro inhibitors have been deposited in a database (Curcumin Research Center) to aid research on anti-SARS-CoV-2 drugs.

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Section: Introductionmentioning

confidence: 99%