Proteases represent common targets in combating infectious diseases including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19 and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies unveil a proposal of a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases.

Dengue fever, caused by the dengue virus (DENV), presents a significant global health challenge, especially in tropical and subtropical regions. In 2024, dengue cases in Brazil are four times higher than in 2023, with a significant increase in deaths. This serves as a warning for potential new dengue outbreaks in non-tropical areas. Herein, we explored various aspects of DENV transmission, clinical manifestations, epidemiological trends, and management strategies. DENV transmission involves Aedes mosquitoes as vectors and humans as a host, influenced by temperature, humidity, and precipitation, exacerbated by climate change. Clinical manifestations range from asymptomatic to severe forms such as dengue hemorrhagic fever and dengue shock syndrome, affected by viral serotype and host factors. Common symptoms of dengue include strong headache, body and joint pain, prostration, weakness, pain behind the eyes, rash, and itchy skin. In some cases, especially in children, dengue may initially present with intense diarrhea and vomiting before progressing to more characteristic symptoms. Even patients with mild dengue fever often experience symptoms, particularly weakness, that hinder their ability to perform daily activities. These symptoms can persist for at least one week. We approached several diagnoses that combine clinical symptoms with serological and molecular tests. Prevention strategies implemented in Brazil include vector control, community engagement, and vaccination programs are described and shown to be insufficient to prevent the outbreak in 2024. Climate change drives the geographical expansion of dengue-endemic areas, with recent outbreaks in Europe highlighting the evolving epidemiological landscape. Vigilant and global collaborative efforts are crucial to decrease dengue's impact worldwide.