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.

登革热仍然是一种备受关注的疾病，全球近一半的节肢动物传播疾病病例都是由登革热引起的。由于缺乏有效和有针对性的治疗方法，姑息治疗和采取预防措施仍然是唯一可用的选择。使问题进一步复杂化的是，唯一的登革热疫苗 Dengvaxia® 的失败也对治疗登革热的希望造成了重大打击。然而，人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）蛋白酶抑制剂过去的成功继续鼓励研究人员研究其他病毒蛋白酶靶点。登革热病毒 (DENV) NS2B-NS3 蛋白酶是一个有吸引力的靶标，部分原因是它在多蛋白加工中的作用，也是病毒基因组中最保守的结构域。在 COVID-19 大流行初期，报告了几例登革热和 COVID-19 混合感染病例。在这篇综述中，我们比较了这两种病毒的底物肽残基偏好和蛋白酶子袋内的残基，并分析了这种相似性的重要性。此外，我们试图简述过去六年（2015-2020）抗登革热药物发现的进展，重点关注影响研究的关键发现。