Biology subjects

Gonzalez, J. E. H.

Publications and source records attributed to Gonzalez, J. E. H..

2 recordsLinked to original sources

bioRxiv2025

Inhibition of Chikungunya virus nsP2 protease in vitro by pantinin-1 isolated from scorpion venom

Climate change has enhanced the spread of arboviruses such as Chikungunya virus (CHIKV). CHIKV is a re-emerging virus from the family Togaviridae that has spread globally, causing numerous outbreaks. The lack of antiviral therapy against CHIKV makes it a significant threat to public health. Cleavage of the viral polyprotein depends on the catalytic activity of nsP2, which is essential for viral replication. Due to this critical role, the nsP2 protease is a promising target for antiviral drug development. Animal venom-derived peptides have shown great potential against a variety of diseases, including infections, cancer, and neurodegenerative disorders. In this study, we evaluated the inhibitory effects and properties of pantinin-1, a peptide derived from the scorpion Pandinus imperator with broad antimicrobial activity, against CHIKV nsP2 protease. Pantinin-1 effectively inhibited CHIKV nsP2 protease, with a half-maximal inhibitory concentration (IC50) of 6.4 {+/-} 2.04 {micro}M and complete inhibition at 175 {micro}M. Further analysis revealed that pantinin-1 acts as a competitive inhibitor with low micromolar affinity and showed no toxicity up to 20 {micro}M in cell culture. Lastly, using molecular docking with subsequent molecular dynamics, the protein-peptide interaction was analyzed, and the key residues involved in the interaction with the protease were predicted. These findings highlight the potential inhibitory effect of pantinin-1 as a lead candidate targeting nsP2 protease.

biochemistry↗

bioRxiv2025

Lipid dependence of connexin-32 gap junction channel conformations

Connexin gap junction channels (GJCs) are a family of proteins that connect the cytoplasms of two neighbouring cells and allow direct intercellular exchange of solutes smaller than [~]1 kDa, ensuring metabolic and electrical coupling of tissues. Connexin-32 (Cx32) GJCs mediate intercellular coupling in a variety of tissues, and specifically in the myelinating Schwann cells. Mutations in Cx32, such as W3S, are associated with peripheral neuropathy, X-linked Charcot-Marie-Tooth (CMT1X) disease. Phospholipids and sterols have been shown to regulate permeation through Cx32 GJCs, although the mechanism of regulation of Cx32 and other GJCs by lipids remains poorly understood. Here, we determine the cryo-EM structures of Cx32 GJCs reconstituted in nanodiscs, revealing that phospholipids block the pore of Cx32 GJC by binding to the site formed by N-terminal gating helices. The phospholipid-bound state is contingent on the presence of a sterol molecule bound to a hydrophobic pocket formed by the N-terminus: the N-terminal helix of Cx32 fails to sustain a phospholipid binding site in the absence of cholesterol hemisuccinate. Consistent with this, the CMT1X-linked W3S mutant which has an impaired sterol binding site adopts a conformation of the N-terminus incompatible with phospholipid binding. Our results indicate that different lipid species control connexin channel gating directly by influencing the conformation of the N-terminal gating helix. One-Sentence SummaryLipids modulate the gating helix conformation in connexin-32 channels

biophysics↗