SMALL MOLECULE INHIBITOR FOR BLOCKING SARS-CoV-2 ENTRY

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel and highly pathogenic coronavirus and is the causative agent of COVID-19, an ongoing pandemic that has posed a serious threat to public health and global economy. Thus, there is a pressing need for therapeutic interventions that target essential viral proteins and regulate virus spread and replication. To invade the host cell, the receptor-binding domain (RBD) of SARS-CoV-2 Spike protein binds to the host cell's ACE2 receptor, followed by cleavage events that allow the Spike protein to fuse with the host cell membrane. Thus, the essential role of Spike protein in ACE2 receptor binding and viral fusion makes it a prime target for therapeutic interventions. Method(s): We performed molecular docking and molecular dynamics (MD) simulation-based virtual screening against SARS-CoV-2 RBD/ACE2 interface using a commercial library of 93,835 drug-like compounds. Compounds with promising docking poses and scores were selected for further MD simulation refinement, from which ten lead compounds were identified. Antiviral potencies of ten lead compounds were evaluated against lentiviral vectors pseudotyped with SARS-CoV-2 Spike to down select to a single lead compound, SAI4. ELISA-based assays were employed to determine the binding affinities of SAI4 to recombinant SARS-CoV-2 RBD. Antiviral potential of SAI4 was validated against genuine SARS-CoV-2 in a BSL3 setting. Result(s): We identified SAI4 as a candidate small molecule, which inhibited SARS-CoV-2 pseudovirus entry with IC50 value of ~18 muM. We determined that SAI4 binds RDB with a Kd of ~20 muM. Using cells engineered to express ACE2 and cells that express physiological levels of ACE2, we found that SAI4 inhibited SARS-CoV-2 pseudovirus entry at both engineered and physiological ACE2 levels. We validated the antiviral potential of SAI4 against genuine SARS-CoV-2 and HCoV-NL63. Lastly, we demonstrated antiviral potential of SAI4 against four SARS-CoV-2 variants of concern (alpha, beta, gamma, and delta). Conclusion(s): Using virtual screening, we identified SAI4 as the promising hit compound which displayed inhibitory activities against SARS-CoV-2 entry and its four variants of concern. Thus, our study will pave the way for further development of small molecules for therapeutic targeting of SARS-CoV-2 entry to combat the COVID-19 pandemic.

Hyperglycemia and steroid use increase the risk of rhino-orbito-cerebral mucormycosis regardless of COVID-19 hospitalization: Case-control study, India.

BACKGROUND: In the ongoing COVID-19 pandemic, an increased incidence of ROCM was noted in India among those infected with COVID. We determined risk factors for rhino-orbito-cerebral mucormycosis (ROCM) post Coronavirus disease 2019 (COVID-19) among those never and ever hospitalized for COVID-19 separately through a multicentric, hospital-based, unmatched case-control study across India. METHODS: We defined cases and controls as those with and without post-COVID ROCM, respectively. We compared their socio-demographics, co-morbidities, steroid use, glycaemic status, and practices. We calculated crude and adjusted odds ratio (AOR) with 95% confidence intervals (CI) through logistic regression. The covariates with a p-value for crude OR of less than 0·20 were considered for the regression model. RESULTS: Among hospitalised, we recruited 267 cases and 256 controls and 116 cases and 231 controls among never hospitalised. Risk factors (AOR; 95% CI) for post-COVID ROCM among the hospitalised were age 45-59 years (2·1; 1·4 to 3·1), having diabetes mellitus (4·9; 3·4 to 7·1), elevated plasma glucose (6·4; 2·4 to 17·2), steroid use (3·2; 2 to 5·2) and frequent nasal washing (4·8; 1·4 to 17). Among those never hospitalised, age ≥ 60 years (6·6; 3·3 to 13·3), having diabetes mellitus (6·7; 3·8 to 11·6), elevated plasma glucose (13·7; 2·2 to 84), steroid use (9·8; 5·8 to 16·6), and cloth facemask use (2·6; 1·5 to 4·5) were associated with increased risk of post-COVID ROCM. CONCLUSIONS: Hyperglycemia, irrespective of having diabetes mellitus and steroid use, was associated with an increased risk of ROCM independent of COVID-19 hospitalisation. Rational steroid usage and glucose monitoring may reduce the risk of post-COVID.

Challenges in the management of ENT foreign bodies during COVID-19 Pandemic - Experience at a tertiary care centre. (preprint)

The novel coronavirus disease 2019 (COVID-19) pandemic has put unprecedented challenges on the medical community. ENT surgical procedures are associated with very high risk of transmission of the virus due to aerosol generation. Management of ENT emergencies due to foreign bodies during ongoing COVID-19 was challenging. This is a prospective study done in our tertiary care centre from March 2020 to June 2020, during COVID-19 pandemic, where patients were referred from primary health facility after unsuccessful attempt. The challenges encountered in the management of these cases, precautions taken and protocols followed are being discussed. The foreign bodies should be removed by trained personnel using Personal Protective Equipment taking all precautions to minimize aerosol generating procedures and limit the length of these procedures whenever possible. Additionally, the use of povidone-iodine in varying concentrations is emphasized in reducing the viral load in the aerodigestive tract, thus proving to be safe to both the patients and the treating doctors.