A Mechanism of Action for Hydroxychloroquine and Azithromycin to Inhibit Coronavirus Disease COVID-19

Hydroxychloroquine and azithromycin have clinical promise to treat COVID-19, although its mechanism of action to inhibit the replication of coronavirus is unclear. Using molecular modeling and recent discoveries made by this lab on the structure of nucleic acids, a mechanism of action is developed for hydroxychloroquine (HCQ) and azithromycin (AZR) to inhibit the replication of the coronavirus disease COVID-19. The mechanism involves: (1) binding the Cl end-element of HCQ through ionic means to adjacent phosphate groups of the uracil nucleotide; (2) forming an intermolecular hydrogen bond of an NH group of HCQ to an open oxygen element of uracil; (3) binding OH end group of HCQ through ionic means with adjacent phosphate groups of the adenine nucleotide. The mechanism of action is extended to AZR as a drug delivery vector that collects HCQ and two ions of positive two charge, such as Mg2+, Zn2+ or Ca2+, and delivers the assembly to a secondary structure of single-strand RNA. As with HCQ, the structural biology of AZR is compatible for use as a collection and delivery vesicle including: (1) open access for the Cl end element and the NH group of HCQ to align and bind with Uracil, and (2) the ability to deliver and bind through ionic coupling of the OH end group of HCQ to the adenine nucleotide. The molecular ionic attachment of HCQ to RNA nucleotides enabled by AZR results in the inhibition of the replication capability of the coronavirus disease COVID-19.

A Mechanism of Action for Hydroxychloroquine and Azithromycin to Inhibit Coronavirus Disease COVID-19

Hydroxychloroquine and azithromycin have clinical promise to treat COVID-19, although its mechanism of action to inhibit the replication of coronavirus is unclear. Using molecular modeling and recent discoveries made by this lab on the structure of nucleic acids, a mechanism of action is developed for hydroxychloroquine (HCQ) and azithromycin (AZR) to inhibit the replication of the coronavirus disease COVID-19. The mechanism involves: (1) binding the Cl end-element of HCQ through ionic means to adjacent phosphate groups of the uracil nucleotide; (2) forming an intermolecular hydrogen bond of an NH group of HCQ to an open oxygen element of uracil; (3) binding OH end group of HCQ through ionic means with adjacent phosphate groups of the adenine nucleotide. The mechanism of action is extended to AZR as a drug delivery vector that collects HCQ and two ions of positive two charge, such as Mg2+, Zn2+ or Ca2+, and delivers the assembly to a secondary structure of single-strand RNA. As with HCQ, the structural biology of AZR is compatible for use as a collection and delivery vesicle including: (1) open access for the Cl end element and the NH group of HCQ to align and bind with Uracil, and (2) the ability to deliver and bind through ionic coupling of the OH end group of HCQ to the adenine nucleotide. The molecular ionic attachment of HCQ to RNA nucleotides enabled by AZR results in the inhibition of the replication capability of the coronavirus disease COVID-19.

Connexin26 deafness associated mutations show altered permeability to large cationic molecules

Intercellular communication is important for cochlear homeostasis because connexin26 (Cx26) mutations are the leading cause of hereditary deafness. Gap junctions formed by different connexins have unique selectivity to large molecules, so compensating for the loss of one isoform can be challenging in the case of disease causing mutations. We compared the properties of Cx26 mutants T8M and N206S with wild-type channels in transfected cells using dual whole cell voltage clamp and dye flux experiments. Wild-type and mutant channels demonstrated comparable ionic coupling, and their average unitary conductance was ∼106 and ∼60 pS in 120 mM K+-aspartate− and TEA+-aspartate− solution, respectively, documenting their equivalent permeability to K+ and TEA+. Comparison of cAMP, Lucifer Yellow (LY), and ethidium bromide (EtBr) transfer revealed differences in selectivity for larger anionic and cationic tracers. cAMP and LY permeability to wild-type and mutant channels was similar, whereas the transfer of EtBr through mutant channels was greatly reduced compared with wild-type junctions. Altered permeability of Cx26 to large cationic molecules suggests an essential role for biochemical coupling in cochlear homeostasis.