Identification of potential inhibitors of SARS-CoV-2 S protein-ACE2 interaction by in silico drug repurposing.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus discovered that appeared in Wuhan, China, in December 2019, causes COVID-19 disease which have resulted in cases similar to SARS-atypical pneumonia. As of March 1, 2021, Mexico had reached 2.11 million cases of COVID-19 and 189 thousand deaths; around 116 million cases and 2.57 million deaths are reported worldwide with new cases and increasing mortality every day. To date, there is no specific commercial treatment to control the infection. Repurpose drugs targeting the angiotensin-converting enzyme 2 (ACE2) receptor represents an alternative strategy to block the binding of SARS-CoV-2 protein S and forestall virus adhesion, internalization and replication in the host cell. Methods: Rigid molecular docking was performed using receptor binding domain of the S1 subunit of S protein (RBD S1)-ACE2 (PDB ID: 6VW1) interaction site and 1,283 drugs FDA approved and prescribed by the Mexican Public Health System. The results were analyzed by docking score, frequency of the drug in receptor site and the types of interactions at the binding site residues. Results: About 40 drugs were identified as a potential inhibitor of RBD S1-ACE2 interaction. Within the top-ranked drugs, we identified ipratropium, formoterol and fexofenadine, which stands out as they are used as therapies to treat chronic obstructive pulmonary disease, asthma and virtually any respiratory infection. Conclusions: Our results will serve as the basis for in vitro and in vivo studies to evaluate the potential use of those drugs to generate affordable and convenient therapies to treat COVID-19.

Identification of a novel member of the pH responsive pathway Pal/Rim in Ustilago maydis.

The most important signal transduction mechanism related to environmental pH responses in fungi is the Pal/Rim pathway. Our knowledge of this pathway came initially from studies on Ascomycota species where it is made by seven members divided into two complexes, one located at the plasma membrane, and other at the endosomal membrane. In Basidiomycota sepecies only the homologs of the endosomal membrane complex (genes PalA/Rim20, PalB/ Rim13, and PalC/ Rim23), plus the transcription factor PacC/Rim101 have been identified. In this study, we describe the identification in Ustilago maydis of a gene encoding a Rho-like protein (tentatively named RHO4) as a novel member of this pathway. The RHO4 gene possibly plays, among other functions, a role in the second proteolytic cleavage that leads to the activation of the transcription factor PacC/Rim101. Mutants in this gene showed a pleiotropic phenotype, displaying similar characteristics to the Pal/Rim mutants, such as a lower growth rate at alkaline pH, high sensitivity to ionic and osmotic stresses, and impairment in protease secretion, but no alteration of the yeast-to-mycelium dimorphic transition induced by acid pH whereas it has a function in the dimorphic transition induced by fatty acids.