Purification and characterisation of heparin-like sulfated polysaccharides with potent anti-SARS-CoV-2 activity from snail mucus of Achatina fulica.

Heparin-like sulfated polysaccharide, acharan sulfate, was purified from the mucus of an African giant snail with unique sulfated glycosaminoglycans (GAGs). This study reported on finding novel and safe heparin resources from Achatina fulica for further use as well as easy isolation and purification of the active fraction from the initial raw material. Its structure was characterised by a strong-anion exchange combined with high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) spectroscopy. The results indicated that the potential acharan sulfate fraction is a glycosaminoglycan composed of several repeating disaccharide units, namely, of →4)-α-IdoA(2S)(1→4)-α-GlcNAc/GlcNAc(6S)/GlcNSO3(6S)(1→, and hence, presents heterogeneity regarding negative net charge density. Furthermore, the heparinase digests inhibit the binding of SARS-CoV-2 spike protein to the ACE2 receptor. In summary, the acharan sulfate presented in this work has shown its great potential for application in the preparation of sulfated polysaccharides as an alternative to heparin with important biological activity.

Molecular dynamics study on the strengthening behavior of Delta and Omicron SARS-CoV-2 spike RBD improved receptor-binding affinity.

The COVID-19 pandemic caused by a virus that can be transmitted from human to human via air droplets has changed the quality of life and economic systems all over the world. The viral DNA has mutated naturally over time leading to the diversity of coronavirus victims which has posed a serious threat to human security on a massive scale. The current variants have developed in a dominant way and are considered "Variants of Concern" by the World Health Organization (WHO). In this work, Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529) variants were obtained to evaluate whether naturally occurring mutations have strengthened viral infectivity. We apply reliable in silico structural dynamics and energetic frameworks of the mutated S-RBD protein for ACE2-binding to analyze and compare the structural information related to the wild-type. In particular, the hotspot residues at Q493, Q498, and N501 on the S-RBD protein were determined as contributing factors to the employment stability of the relevant binding interface. The L452R mutation induces an increment of the hydrogen bonds formed by changing the Q493 environment for ACE2 binding. Moreover, the Q493K exchange in Omicron enables the formation of two additional salt bridges, leading to a strong binding affinity by increased electrostatic interaction energy. These results could be used in proposing concrete informative data for a structure-based design engaged in finding better therapeutics against novel variants.

Mutational scanning of spike RBD protein for enhanced ACE2 affinity emerging Southeast Asia in the late transmission phase.

The COVID-19 pandemic has changed the quality of life and economic systems all over the world, as the virus can be transmitted from human to human via air-droplets. Since the SARS-CoV-2 virus was first identified in 2019, the virus has naturally mutated over time. Southeast Asia is one of the areas in the world that has implemented various procedures and measures to slow down the disease outbreaks. The first cluster of COVID-19 was identified from the tourist-travel history, and then the diversity of coronavirus victims has posed a serious issue of human security on a massive scale. To evaluate whether or not naturally occurring mutations have strengthened the infectivity of SARS-CoV-2, we computed in silico the structural dynamics of the RBD-spike protein mutation enhancing ACE2-binding. When considering emerging variations in Southeast Asia, 14 dominant mutations were analyzed by applying the structural and energetic characterization using MD simulations. The ones in the RBD region displayed higher affinity to ACE2 due to the improved interfacial stability of the RBD ß-strand surrounding the ACE2 across salt bridge hotspots. The binding hotspots and structurally conserved conformational-epitopes have been identified, which are deleterious for RBD mutation and ACE2 binding. We present an interactive visualization to facilitate the development of effective neutralizing agents for vaccination, prevention and treatment.

Molecular modelling investigation for drugs and nutraceuticals against protease of SARS-CoV-2.

The widespread problem of a 2019-novel coronavirus (SARS-CoV-2) strain outbreak in Wuhan, China has prompted a search for new drugs to protect against and treat this disease. It is necessary to immediately investigate this due to the mutation of the viral genome and there being no current protective vaccines or therapeutic drugs. Molecular modelling and molecular docking based on in silico screening strategies were employed to determine the potential activities of seven HIV protease (HIV-PR) inhibitors, two flu drugs, and eight natural compounds. The computational approach was carried out to discover the structural modes with a high binding affinity for these drugs on the homology structure of the Wuhan coronavirus protease (SARS-CoV-2 PR). From the theoretical calculations, all the drugs and natural compounds demonstrated various favorable binding affinities. An interesting finding was that the natural compounds tested had a higher potential binding activity with the pocket sites of SARS-CoV-2 PR compared to the groups of HIV-PR inhibitors. The binding modes of each complex illustrated between the drugs and compounds interacted with the functional group of amino acids in the binding pocket via hydrophilic, hydrophobic, and hydrogen bond interactions using the molecular dynamics simulation technique. This result supports the idea that existing protease inhibitors and natural compounds could be used to treat the new coronavirus. This report sought to provide fundamental knowledge as preliminary experimental data to propose an existing nutraceutical material against viral infection. Collectively, it is suggested that molecular modelling and molecular docking are suitable tools to search and screen for new drugs and natural compounds that can be used as future treatments for viral diseases.