A short survey of dengue protease inhibitor development in the past 6 years (2015–2020) with an emphasis on similarities between DENV and SARS-CoV-2 proteases

Abstract

Dengue remains a disease of significant concern, responsible for nearly half of all arthropod-borne disease cases across the globe. Due to the lack of potent and targeted therapeutics, palliative treatment and the adoption of preventive measures remain the only available options. Compounding the problem further, the failure of the only dengue vaccine, Dengvaxia®, also delivered a significant blow to any hopes for the treatment of dengue fever. However, the success of Human Immuno-deficiency Virus (HIV) and Hepatitis C Virus (HCV) protease inhibitors in the past have continued to encourage researchers to investigate other viral protease targets. Dengue virus (DENV) NS2B-NS3 protease is an attractive target partly due to its role in polyprotein processing and also for being the most conserved domain in the viral genome. During the early days of the COVID-19 pandemic, a few cases of Dengue-COVID 19 co-infection were reported. In this review, we compared the substrate-peptide residue preferences and the residues lining the sub-pockets of the proteases of these two viruses and analyzed the significance of this similarity. Also, we attempted to abridge the developments in anti-dengue drug discovery in the last six years (2015–2020), focusing on critical discoveries that influenced the research.

Flavonoids Biosynthesis in Plants as a Defense Mechanism: Role and Function Concerning Pharmacodynamics and Pharmacokinetic Properties

“…Against the dengue virus, baicalein and baicalin (DENV). By eliminating extracellular viral particles, they prevented the growth of DENV-2.Baicalein demonstrated a strong affinity for the DENV NS3/NS2B protein (À7.5 kcal/mol) and the NS5 protein (À8.6 kcal/mol), according to in silico studies [198][199][200][201]. Baicalin may prevent CHIKV infection because of its high binding affinity (À9.8 kcal/mol) for the CHIKV nsP3 protein.…”

Recent Advances on Targeting Proteases for Antiviral Development

“…Their genomes are composed of a single-stranded RNA, encoding a single polyprotein that acts as a precursor to other viral proteins. A two-component viral protease, NS2B-NS3, is a serine protease formed from the non-structural protein NS3 and the NS2B co-factor, that cleaves the precursor polyprotein into individual proteins required for viral replication [ 43 , 44 ]. This protease belongs to the trypsin superfamily with a preference for substrates with dibasic residues, such as arginine and lysine, and its active site contains a highly conserved catalytic triad composed of His51, Asp75 and Ser135 residues [ 45 , 46 , 47 ].…”

Repositioning of anti-dengue compounds against SARS-CoV-2 as viral polyprotein processing inhibitor

“…However, experimentally validated anti-dengue compounds were not comprehensively explored against SARS-CoV-2 M pro . In recent work, Murtuja et al demonstrated the development of DENV inhibitors with a targeted comparison of a protease between DENV and SARS-CoV-2 [ 62 ].…”

“…Moreover, experimental findings of inhibitors were also validated using molecular dynamics simulation to understand the molecular level interaction between proteins and small molecules [54]. Among natural compounds or their derivatives, flavonoid compounds were extensively used in various computation screening studies against M pro [55][56][57][58][59][60][61][62]. Many antiviral compounds were evaluated computationally against SARS CoV-2 M pro to detect their repurposing effect.…”