Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent of the pandemic disease COVID-19, which is so far without efficacious treatment. The discovery of therapy reagents for treating COVID-19 are urgently needed, and the structures of the potential drug-target proteins in the viral life cycle are particularly important. SARS-CoV-2, a member of the Orthocoronavirinae subfamily containing the largest RNA genome, encodes 29 proteins including nonstructural, structural and accessory proteins which are involved in viral adsorption, entry and uncoating, nucleic acid replication and transcription, assembly and release, etc. These proteins individually act as a partner of the replication machinery or involved in forming the complexes with host cellular factors to participate in the essential physiological activities. This review summarizes the representative structures and typically potential therapy agents that target SARS-CoV-2 or some critical proteins for viral pathogenesis, providing insights into the mechanisms underlying viral infection, prevention of infection, and treatment. Indeed, these studies open the door for COVID therapies, leading to ways to prevent and treat COVID-19, especially, treatment of the disease caused by the viral variants are imperative.

The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has caused devastating impacts on the public health and the global economy. Rapid viral antigenic evolution has led to the continual generation of new variants. Of special note is the recently expanding Omicron subvariants that are capable of immune evasion from most of the existing neutralizing antibodies (nAbs). This has posed new challenges for the prevention and treatment of COVID-19. Therefore, exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In sharp contrast to the massive accumulation of mutations within the SARS-CoV-2 receptor-binding domain (RBD), the S2 fusion subunit has remained highly conserved among variants. Hence, S2-based therapeutics may provide effective cross-protection against new SARS-CoV-2 variants. Here, we summarize the most recently developed broad-spectrum fusion inhibitors (e.g., nAbs, peptides, proteins, and small-molecule compounds) and candidate vaccines targeting the conserved elements in SARS-CoV-2 S2 subunit. The main focus includes all the targetable S2 elements, namely, the fusion peptide, stem helix, and heptad repeats 1 and 2 (HR1-HR2) bundle. Moreover, we provide a detailed summary of the characteristics and action-mechanisms for each class of cross-reactive fusion inhibitors, which should guide and promote future design of S2-based inhibitors and vaccines against new coronaviruses.

Background: Fluid resuscitation is the cornerstone of sepsis management, however, the choice between balanced crystalloid solutions and normal saline remains debated. This meta-analysis aimed to compare the efficacy of balanced solutions versus saline for fluid resuscitation in adult patients with sepsis. Methods: A systematic literature search was performed in PubMed, Embase, Scopus, and other relevant sources. Retrieved studies were rigorously screened according to predefined inclusion and exclusion criteria. Data from the included studies were extracted for analysis. The primary outcome was defined as mortality rate. Secondary outcomes included acute kidney injury (AKI), hyperchloremia, renal replacement therapy (RRT), ICU-free days, ventilator-free days, vasopressor-free days. The study protocol was registered with PROSPERO (CRD420261368142). Results: A total of eight studies (8,173 patients; 4,056 assigned to balanced solutions, 4,117 to saline) met the inclusion criteria. In the primary analysis restricted to seven randomized controlled trials, balanced solutions were associated with significantly lower mortality than saline (RR 0.92; 95% CI 0.86–0.98; P = 0.01; I ² = 37%), and a sensitivity analysis incorporating a post-hoc observational study yielded consistent results (RR 0.91; 95% CI 0.85–0.97). Balanced solutions were also associated with lower incidences of AKI (RR 0.86; 95% CI 0.78–0.96; P = 0.004), hyperchloremia (RR 0.68; 95% CI 0.52–0.90; P = 0.007), and RRT requirement (RR 0.74; 95% CI 0.56–1.00; P = 0.05), and with a greater number of ICU-free, ventilator-free, and vasopressor-free days (all P < 0.05). Conclusion: In adult patients with sepsis, treatment with balanced crystalloid solutions for fluid resuscitation significantly reduces mortality (moderate certainty), decreases kidney-related adverse events, and better maintains electrolyte balance, thereby improving patient outcomes. These findings support the preferential use of balanced crystalloids over saline in this population. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261368142 , identifier CRD420261368142.

Objective: The adjunctive therapeutic value of vitamin C in sepsis or septic shock patients remains controversial. This study aimed to evaluate the therapeutic efficacy and safety of intravenous administration of vitamin C in sepsis or septic shock patients through meta-analysis. Methods: Relevant literature was searched in PubMed, Embase, and Scopus databases and other related databases. The primary outcome was 28-day mortality. Secondary outcomes included duration and total dose of vasopressors, change in sequential organ failure assessment (SOFA) scores from baseline to the earliest reported time point between 72 and 96 h (ΔSOFA), hospital length of stay, intensive care unit length of stay, urine output in the 24-h, and incidence of adverse events. Results: Fourteen randomized controlled trials enrolling 1,958 patients were eligible for assessment. Meta-analysis demonstrated that intravenous vitamin C reduced 28-day mortality in sepsis or septic shock patients compared to the control group (RR 0.70; 95% CI 0.53 to 0.93; P = 0.02; I ² = 52%), based on low quality of evidence, and subgroup analysis showed the benefit was driven by single-center studies, not observed in multicenter trials. Vitamin C shortened the duration of vasopressor use (SMD = −0.42, 95% CI −0.77 to −0.08, P = 0.02) and was associated with a greater reduction in SOFA score (MD = −1.04, 95% CI −1.83 to −0.25, P = 0.01), but did not reduce vasopressor dose, length of stay, or 24-h urine output. No significant adverse events were reported. Conclusion: This meta-analysis suggests that intravenous vitamin C might be associated with reduced mortality in sepsis, but the benefit was not confirmed in low-risk-of-bias multicenter trials and was primarily driven by single-center studies. Intravenous vitamin C appeared safe. Given the exploratory nature of these subgroup analyses and the data-driven thresholds used, high-quality, multicenter RCTs are warranted. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/view/CRD4204261367808 , identifier CRD4204261367808.