Biology, Engineering, Medicine and Science Reports

Molecular Profiling of Neprilysin Expression and its Interactions with SARS-CoV-2 Spike Proteins to Develop Evidence Base Pharmacological Approaches for Therapeutic Intervention

Arun HS Kumar — Mon, 25 Oct 2021 00:00:00 -0400

Introduction: Neprilysin due to its peptidase activity is involved in several physiological and pathological processes. Recently our group has reported the association of neprilysin with angiotensin-converting enzyme 2 (ACE2) network proteins which facilitate the entry of SARS-CoV-2 virus. The potential role of neprilysin beyond its peptidase activity is not known. Materials and Methods: Using the established sequence analysis and molecular docking tools, this study evaluated the molecular profile of neprilysin interaction with SARSCoV- 2 virus proteins. Results: Human neprilysin protein showed a significant sequence similarity with SARS-CoV-2 spike protein, which was further confirmed by observation of considerable interaction in the molecular docking. Human neprilysin protein was also found to additionally interact with SARS-CoV-2 proteins facilitating virus replication. The potential of neprilysin inhibitors (Sacubitril and Sacubitrilat) to interfere with neprilysin and SARS-CoV-2 proteins interactions was assessed. The neprilysin inhibitors showed binding efficacy within therapeutically feasible concentration range (1 to 150 uM). Conclusion: This study while reporting a novel role of neprilysin as potential receptor for SARS-CoV-2 virus, highlights the merit in assessing clinical efficacy of neprilysin inhibitors for the management of SARS-CoV-2 infection.

Network Pharmacology Analysis of Orally Bioavailable SARS-CoV-2 Protease Inhibitor Shows Synergistic Targets to Improve Clinical Efficacy

Arun HS Kumar — Mon, 25 Oct 2021 00:00:00 -0400

Introduction: Orally bioavailable SARS-CoV-2 antiviral drugs will significantly improve the clinical management of the disease. PF07321332 (PF32) one such orally bioavailable SARSCoV- 2 protease inhibitor which can be helpful to prevent viral replication in the host. Materials and Methods: Hence this study evaluated the network pharmacology of PF32 using established methods to predict its potential safety and efficacy. Results: PF32 was selective against SARS-CoV-2 proteases without any affinity against SARS-CoV-2 RNA polymerase or its spike protein. While PF32 showed pharmacologically relevant affinity against several targets in human tissues. The target profiling of PF32 indicated a fourfold selectivity towards several proteases in human tissues with an affinity (IC₅₀) ranging from 26 to 41 nM. Conclusion: The predicted inhibitory effects of PF32 against both host and viral proteases may have synergistic effects for superior clinical efficacy.

Modelling the Efficacy of Neprilysin from Various Species in Degrading Different Amyloid-β peptides: Potential Application in Development of Therapeutics for Alzheimer’s Disease

Arun HS Kumar — Mon, 25 Oct 2021 00:00:00 -0400

ABSTRACT Recombinant neprilysin due to its degradation potential against Amyloid-β (Aβ) peptides has been looked at as a potential therapeutic candidate for treating Alzheimer’s disease (AD). However the enzymatic activity of neprilysin against different Aβ peptides can variable which significantly limits the therapeutic optimization. Using the molecular interaction analysis and modelling it against the known enzyme-substrate kinetics, this study developed a novel approach to predicting biosimilar enzyme-substrate kinetics. The known enzyme-substrate kinetics of human recombinant neprilysin with Aβ_1-40 peptide was used as the prototype to assess the affinity and efficacy of various inter and intra-species neprilysin- Aβ peptide enzyme kinetics based on the relative molecular interaction analysis. Significant inter and intra-species variations in neprilysin- Aβ peptide enzyme kinetics was observed which further validated the need for optimizing enzyme kinetics tailored to specific substrate degradation. The novel enzyme kinetics modelling approach described in this study can be helpful in the developing of recombinant enzymes/peptides for personalised therapeutic applications.

Rapid Transformational Therapy (RTT): An Emerging Non-invasive Therapeutic Modality

Savitha Raveendran, Chandrasekaran Kaliaperumal — Mon, 25 Oct 2021 00:00:00 -0400

We write to highlight an emerging non-invasive therapeutic option that can be potentially used for various medical ailments. RTT is Rapid Transformational Therapy, a hybrid therapy developed by Marisa Peer in England, UK.1 It combines the best principles of hypnotherapy, cognitive behavioural therapy (CBT), Neuro- Linguistic Programming that offers fast effective results for a range of psychological, psychiatric and physical conditions. As opposed to traditional therapies, RTT is a solution-focussed treatment offering rapid, effective and long-lasting change usually within one (or within three maximum) session. RTT embraces the positive aspects of all the above techniques that are known to produce a transformative effect on the clients. Hypnotherapy uses trance, regression and hypnotic conditioning. RTT goes beyond this process, Marisa identified that regardless of their issue, in sessions clients benefitted from her applying a particular set of techniques over and over again. These insights provided the foundations for RTT to emerge as a distinctive approach.