SPIKENET: An Evidence-Based Therapy for Long COVID.

The COVID-19 pandemic has been one of the most impactful events in our lifetime, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple SARS-CoV-2 variants were reported globally, and a wide range of symptoms existed. Individuals who contract COVID-19 continue to suffer for a long time, known as long COVID or post-acute sequelae of COVID-19 (PASC). While COVID-19 vaccines were widely deployed, both unvaccinated and vaccinated individuals experienced long-term complications. To date, there are no treatments to eradicate long COVID. We recently conceived a new approach to treat COVID in which a 15-amino-acid synthetic peptide (SPIKENET, SPK) is targeted to the ACE2 receptor binding domain of SARS-CoV-2, which prevents the virus from attaching to the host. We also found that SPK precludes the binding of spike glycoproteins with the receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) of a coronavirus, murine hepatitis virus-1 (MHV-1), and with all SARS-CoV-2 variants. Further, SPK reversed the development of severe inflammation, oxidative stress, tissue edema, and animal death post-MHV-1 infection in mice. SPK also protects against multiple organ damage in acute and long-term post-MHV-1 infection. Our findings collectively suggest a potential therapeutic benefit of SPK for treating COVID-19.

Acute and Long COVID Intestinal Changes in an Experimental Model of Coronavirus in Mice.

The COVID-19 pandemic, which emerged in early 2020, has had a profound and lasting impact on global health, resulting in over 7.0 million deaths and persistent challenges. In addition to acute concerns, there is growing attention being given to the long COVID health consequences for survivors of COVID-19 with documented cases of cardiovascular abnormalities, liver disturbances, lung complications, kidney issues, and noticeable cognitive deficits. Recent studies have investigated the physiological changes in various organs following prolonged exposure to murine hepatitis virus-1 (MHV-1), a coronavirus, in mouse models. One significant finding relates to the effects on the gastrointestinal tract, an area previously understudied regarding the long-lasting effects of COVID-19. This research sheds light on important observations in the intestines during both the acute and the prolonged phases following MHV-1 infection, which parallel specific changes seen in humans after exposure to SARS-CoV-2. Our study investigates the histopathological alterations in the small intestine following MHV-1 infection in murine models, revealing significant changes reminiscent of inflammatory bowel disease (IBD), celiac disease. Notable findings include mucosal inflammation, lymphoid hyperplasia, goblet cell hyperplasia, and immune cell infiltration, mirroring pathological features observed in IBD. Additionally, MHV-1 infection induces villous atrophy, altered epithelial integrity, and inflammatory responses akin to celiac disease and IBD. SPIKENET (SPK) treatment effectively mitigates intestinal damage caused by MHV-1 infection, restoring tissue architecture and ameliorating inflammatory responses. Furthermore, investigation into long COVID reveals intricate inflammatory profiles, highlighting the potential of SPK to modulate intestinal responses and restore tissue homeostasis. Understanding these histopathological alterations provides valuable insights into the pathogenesis of COVID-induced gastrointestinal complications and informs the development of targeted therapeutic strategies.

Mechanism of Multi-Organ Injury in Experimental COVID-19 and Its Inhibition by a Small Molecule Peptide.

Severe disease from SARS-CoV-2 infection often progresses to multi-organ failure and results in an increased mortality rate amongst these patients. However, underlying mechanisms of SARS- CoV-2-induced multi-organ failure and subsequent death are still largely unknown. Cytokine storm, increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs contribute to the pathogenesis of COVID-19. One potential consequence of immune/inflammatory events is the acute progression of generalized edema, which may lead to death. We, therefore, examined the involvement of water channels in the development of edema in multiple organs and their contribution to organ dysfunction in a Murine Hepatitis Virus-1 (MHV-1) mouse model of COVID-19. Using this model, we recently reported multi-organ pathological abnormalities and animal death similar to that reported in humans with SARS-CoV-2 infection. We now identified an alteration in protein levels of AQPs 1, 4, 5, and 8 and associated oxidative stress, along with various degrees of tissue edema in multiple organs, which correlate well with animal survival post-MHV-1 infection. Furthermore, our newly created drug (a 15 amino acid synthetic peptide, known as SPIKENET) that was designed to prevent the binding of spike glycoproteins with their receptor(s), angiotensin- converting enzyme 2 (ACE2), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (SARS-CoV-2 and MHV-1, respectively), ameliorated animal death and reversed altered levels of AQPs and oxidative stress post-MHV-1 infection. Collectively, our findings suggest the possible involvement of altered aquaporins and the subsequent edema, likely mediated by the virus-induced inflammatory and oxidative stress response, in the pathogenesis of COVID- 19 and the potential of SPIKENET as a therapeutic option.

Catalytically active lead(ii)-imidazolium coordination assemblies with diversified lead(ii) coordination geometries.

Five Pb(ii)-imidazolium carboxylate coordination assemblies with novel structural motifs were derived from the reaction between the corresponding flexible, semi flexible or rigid imidazolium carboxylic acid ligands and lead nitrate. The imidazolium linker present in these molecules likely plays a triple role such as the counter ion to balance the metal charge, the ligand being an integral part of the final product and the catalyst facilitating carbon-carbon bond formation reaction. These lead-imidazolium coordination assemblies exhibit, variable chemical and thermal stabilities, as well as catalytic activity. These newly prepared catalysts are highly active towards benzoin condensation reactions with good functional group tolerance.

Photoluminescent calcium azolium carboxylates with diversified calcium coordination geometry and thermal stability.

Despite the popularity and versatility of transition-metal­azolium carboxylate coordination polymers, there are very few examples of group 2 complexes supported by azolium carboxylate ligands in the literature, and there are none featuring luminescent calcium azolium carboxylates. New ionic calcium coordination networks, {[Ca2(L(1))2(H2O)4](Br)4·6H2O}∞ (1), {[(L(3))2Ca(H2O)2]2(Br)2}∞ (3), {[(L(4))2Ca(H2O)2]2(Br)2}∞ (4), and {[(L(5))2Ca3(Na)(H2O)9(Cl)](Br)6·2H2O}∞ (5) along with binuclear {[Ca2(L(2))2(H2O)9](Br)4·4H2O} (2), and trinuclear {[(L(6))2Ca3(H2O)9](Br)6} (6) were isolated from the reaction between the corresponding azolium carboxylates and calcium carbonate in aqueous solution. 1­6 were characterized by FT-IR, NMR, TGA, UV-vis, fluorescence and single crystal X-ray diffraction techniques. Interestingly, the first tetra-cationic binuclear calcium 2 was isolated using L(2)H2Br2 and hexa-cationic trinuclear calcium 6 was isolated using L(6)H3Br3. The 3D coordination polymers 1 and 4 were derived with the help of L(1)H2Br2 and L(4)H2Br2, respectively, through Br···H hydrogen bonding. The 3D MOF 3 with rhomboidal channels was constructed using L(3)H2Br2, where the channel size is about 4.8 × 2.9 nm. 5 was isolated as a rare 1D coordination polymer. The choice of azolium carboxylates in these solids not only changes the topology of the network but also affects the chemistry exhibited by the network. Calcium azolium carboxylate assemblies 1­4 and 6 exhibit interesting solid-state photoluminescence properties, driven by azolium carboxylate ligands. Variation of the bridging chromophore produced significant effects on the fluorescence properties. 1­4 and 6 represent the first examples of luminescent calcium azolium carboxylate complexes. As can be seen in the six metal­organic assemblies presented in this report, a combination of carboxylate groups and steric hindrance affects the topology and physical properties of the resultant solids.

Luminescent imidazolium carboxylate supported aggregate and infinite coordination networks of copper and zinc.

The new copper dimer [LCu(DMF)]2(NO3)4(H2O)(DMF)2 (4), where L = [{1,1'-(CH2)2-C14H8)-3,3'-(CH2CO2)2}{(HCN)2CH}], and porous coordination polymers [{L2Cu(OH2)2}2Br2]x (5) and [{L2Zn(OH2)2}2Br2]x (6) have been isolated from reactions of luminescent imidazolium carboxylate ligand, LH2Br2 (3) and the corresponding metal precursors. The reaction between Cu(NO3)2·3H2O and LH2Br2 (3) in DMF at 100 °C yielded bluish green crystals of tetracationic discrete copper dimer 4, the structure of which contains a rare tetracationic [(DMF)Cu(ii)]2 dimer unit that is bridged by four carboxylates of two L in a "paddle-wheel" structure. When the reaction was carried out in the presence of a water-ethanol-methanol mixture, light green crystals of 5 were obtained. Molecule 5 comprises two-dimensional (2D) porous coordination polymeric sheets consisting of unique symmetrical dinuclear [(C(O)O)Cu(OH2)2(O(O)C)2]2 building blocks, which are connected by imidazolium anthracene spacers. The infinite 2D porous coordination polymeric sheets are further linked by significant intermolecular hydrogen-bonding interactions by bromide anions to form a three-dimensional supramolecular framework. Interestingly, the reaction between zinc dust and LH2Br2 (3) in H2O at room temperature gave similar structural features to those in 5, though they differ in terms of C-O bond distances and M-O-C angles. The solution-state UV-visible absorption spectra of 2-6 in water exhibits the comparable absorption pattern with decrease in the intensity of absorption from 5, 4, 3, 6 and 2, while the solid-state UV-visible absorption spectra of 2-6 are significantly different from the solution-state UV-visible absorption spectra. The considerable change in the fluorescent emission was observed upon complexation of 3 with corresponding metal precursors and the fluorescent emission was shifted towards the red region in the order of 2, 3, 6, 4 and 5 in water.

Crystallization and preliminary X-ray crystallographic analysis of ß-ketoacyl-ACP synthase I (XoFabB) from Xanthomonas oryzae pv. oryzae.

The proteins in the fatty-acid synthesis pathway in bacteria have significant potential as targets for the development of antibacterial agents. An essential elongation step in fatty-acid synthesis is performed by ß-ketoacyl-acyl carrier protein synthase I (FabB). The organism Xanthomonas oryzae pv. oryzae (Xoo) causes a destructive bacterial blight disease of rice. The XoFabB protein from Xoo was expressed, purified and crystallized for the three-dimensional structure determination that is essential for the development of specific inhibitors of the enzyme. An XoFabB crystal diffracted to 3.0 Å resolution and belonged to the tetragonal space group P4(1), with unit-cell parameters a = b = 82.2, c = 233.2 Å. Assuming that the crystallographic structure contains four molecules in the asymmetric unit, the corresponding V(M) would be 2.18 Å(3) Da(-1) and the solvent content would be 43.5%. The initial structure was determined by the MOLREP program with an R factor of 44.0% and does contain four monomers in the asymmetric unit.