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Viral Proteases: Modulation of Immune Responses and Antiviral Therapies

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 7185

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Special Issue Editor

Dr. Gisselle N. Medina

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Guest Editor

Foreign Animal Disease, United States Department of Agriculture, The Bronx, NY 10474, USA
Interests: virology; virus–host interactions; vaccines; innate immunity; RNA virus; DNA virus; foreign animal diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viruses encode one or more proteases involved in different functions, such as the processing of viral polyproteins, viral maturation and the targeting of host factors, in order to modulate different aspects of the host immune response. Viral proteases and their interaction with the host include the targeting of antiviral effector proteins, the modulation of antiviral signals, the targeting of nuclear–cytoplasmic transport, etc. These functions require enzymatic and non-enzymatic functions and the identification of the molecular determinants involved in these functions are critical for the discovery of novel inhibitors that could serve as targets for therapeutic interventions.

In this Special Issue, we will focus on the most recent advances related to the structure, proteolytic activity, non-proteolytic activity and substrate specificity of viral proteases, and their contribution in regulating immune responses, virulence and pathogenicity. This Special Issue will also focus on new developments in the use of protease inhibitors as antiviral therapies.

Dr. Gisselle N. Medina
Guest Editor

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Keywords

viral proteases
innate immunity
virus–host interactions
protease inhibitors
virulence

Published Papers (4 papers)

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Research

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18 pages, 4359 KiB

Open AccessArticle

Natural Polymorphisms D60E and I62V Stabilize a Closed Conformation in HIV-1 Protease in the Absence of an Inhibitor or Substrate

by Trang T. Tran and Gail E. Fanucci

Viruses 2024, 16(2), 236; https://doi.org/10.3390/v16020236 - 02 Feb 2024

Viewed by 662

Abstract

HIV infection remains a global health issue plagued by drug resistance and virological failure. Natural polymorphisms (NPs) contained within several African and Brazilian protease (PR) variants have been shown to induce a conformational landscape of more closed conformations compared to the sequence of subtype B prevalent in North America and Western Europe. Here we demonstrate through experimental pulsed EPR distance measurements and molecular dynamic (MD) simulations that the two common NPs D60E and I62V found within subtypes F and H can induce a closed conformation when introduced into HIV-1PR subtype B. Specifically, D60E alters the conformation in subtype B through the formation of a salt bridge with residue K43 contained within the nexus between the flap and hinge region of the HIV-1 PR fold. On the other hand, I62V modulates the packing of the hydrophobic cluster of the cantilever and fulcrum, also resulting in a more closed conformation. Full article

(This article belongs to the Special Issue Viral Proteases: Modulation of Immune Responses and Antiviral Therapies)

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17 pages, 4462 KiB

Open AccessArticle

Mass Spectral Analyses of Salmonella Myovirus SPN3US Reveal Conserved and Divergent Themes in Proteolytic Maturation of Large Icosahedral Capsids

by Aaron Scheuch, Sara A. M. Moran, Julia N. Faraone, Sophia R. Unwin, Gialinh Vu, Andrea Denisse Benítez, Nurul Humaira Mohd Redzuan, Dana Molleur, Sammy Pardo, Susan T. Weintraub and Julie A. Thomas

Viruses 2023, 15(3), 723; https://doi.org/10.3390/v15030723 - 10 Mar 2023

Cited by 1 | Viewed by 1470

Abstract

Salmonella myovirus SPN3US has a T = 27 capsid composed of >50 different gene products, including many that are packaged along with the 240 kb genome and ejected into the host cell. Recently, we showed that an essential phage-encoded prohead protease gp245 is responsible for cleavage of proteins during SPN3US head assembly. This proteolytic maturation step induces major changes in precursor head particles, enabling them to expand and undergo genome packaging. To comprehensively define the composition of the mature SPN3US head and elucidate how it is modified by proteolysis during assembly, we conducted tandem mass spectrometry analysis of purified virions and tailless heads. Fourteen protease cleavage sites were identified in nine proteins, including eight sites not previously identified in head proteins in vivo. Among these was the maturation cleavage site of gp245 which was identical to the autocleavage site we had previously identified in purified recombinant gp245. Our findings underscore the value of employing multiple mass spectrometry-based experimental strategies as a way to enhance the detection of head protein cleavage sites in tailed phages. In addition, our results have identified a conserved set of head proteins in related giant phages that are similarly cleaved by their respective prohead proteases, suggesting that these proteins have important roles in governing the formation and function of large icosahedral capsids. Full article

(This article belongs to the Special Issue Viral Proteases: Modulation of Immune Responses and Antiviral Therapies)

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15 pages, 2745 KiB

Open AccessArticle

TMPRSS2 Is Essential for SARS-CoV-2 Beta and Omicron Infection

by Kristin Metzdorf, Henning Jacobsen, Marina C. Greweling-Pils, Markus Hoffmann, Tatjana Lüddecke, Felicitas Miller, Lars Melcher, Amy M. Kempf, Inga Nehlmeier, Dunja Bruder, Marek Widera, Sandra Ciesek, Stefan Pöhlmann and Luka Čičin-Šain

Viruses 2023, 15(2), 271; https://doi.org/10.3390/v15020271 - 18 Jan 2023

Cited by 22 | Viewed by 3508

Abstract

The COVID-19 pandemic remains a global health threat and novel antiviral strategies are urgently needed. SARS-CoV-2 employs the cellular serine protease TMPRSS2 for entry into lung cells, and TMPRSS2 inhibitors are being developed for COVID-19 therapy. However, the SARS-CoV-2 Omicron variant, which currently dominates the pandemic, prefers the endo/lysosomal cysteine protease cathepsin L over TMPRSS2 for cell entry, raising doubts as to whether TMPRSS2 inhibitors would be suitable for the treatment of patients infected with the Omicron variant. Nevertheless, the contribution of TMPRSS2 to the spread of SARS-CoV-2 in the infected host is largely unclear. In this study, we show that the loss of TMPRSS2 strongly reduced the replication of the Beta variant in the nose, trachea and lung of C57BL/6 mice, and protected the animals from weight loss and disease. The infection of mice with the Omicron variant did not cause disease, as expected, but again, TMPRSS2 was essential for efficient viral spread in the upper and lower respiratory tract. These results identify the key role of TMPRSS2 in SARS-CoV-2 Beta and Omicron infection, and highlight TMPRSS2 as an attractive target for antiviral intervention. Full article

(This article belongs to the Special Issue Viral Proteases: Modulation of Immune Responses and Antiviral Therapies)

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Review

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29 pages, 10661 KiB

Open AccessReview

Recent Advances on Targeting Proteases for Antiviral Development

by Pedro Henrique Oliveira Borges, Sabrina Baptista Ferreira and Floriano Paes Silva, Jr.

Viruses 2024, 16(3), 366; https://doi.org/10.3390/v16030366 - 27 Feb 2024

Viewed by 933

Abstract

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. Full article

(This article belongs to the Special Issue Viral Proteases: Modulation of Immune Responses and Antiviral Therapies)

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