Predicting and Designing therapeutics against the Nipah virus

Abstract

Though every outbreak of the Nipah Virus has resulted in high mortality rates (>70% in Southeast Asia), there are no licensed drugs against it. In this study we have considered all 9 Nipah proteins as potential therapeutic targets and computationally identified putative peptides (against G, F, and M proteins) and small molecules inhibitors (against F, G, M, N, and P proteins). The computations include extensive homology/ab initio modelling, peptide design and small molecule docking. An important contribution of this study is the increased structural characterization of Nipah proteins by approximately 90% of what is deposited in the PDB. In addition, we have carried out molecular dynamics simulations on all the designed proteinpeptide complexes to check for stability and to estimate binding strengths. Details, including atomic coordinates of all the proteins and their ligand bound complexes, can be accessed at http://cospi.iiserpune.ac.in/Nipah. Our strategy was to tackle the development of therapeutics on a proteome wide scale and the lead compounds identified could be attractive starting points for drug development. To this end, we have designed 4 peptide inhibitors and predicted 70 small molecules (13 with high confidence) against 3 and 5 Nipah proteins respectively. To counter the threat of drug resistance, we have analyzed the sequences of the viral strains from different outbreaks, to check whether they would be sensitive to the binding of the proposed inhibitors.

Viral pandemic preparedness: A pluripotent stem cell-based machine-learning platform for simulating SARS-CoV-2 infection to enable drug discovery and repurposing

“…In the future, rapid drug repurposing is likely to become vitally important when we are forced to deal with an outbreak of a much more lethal virus. For example, the NIPAH virus (named after Sungai Nipah , a village in the Malaysian Peninsula where pig farmers became ill with encephalitis) has been associated with a human death rate of ~70% 30 compared with the 1% to 2% death rate seen so far with COVID‐19 infection. It would make remarkable good sense to begin planning for the next outbreak now.…”

“…[42][43][44] Small outbreaks continue to occur in Southeast Asia and elsewhere. 30 Importantly, the WHO has gone so far as to identify NIPAH as a prototype for a future pandemic. 42,43 It is our intention now to focus our efforts on creating disease simulations and identifying potentially effective therapies for all 10 of the WHO listed diseases.…”

“…The NIPAH viral genome has been validated and there are currently no effective treatments 42‐44 . Small outbreaks continue to occur in Southeast Asia and elsewhere 30 . Importantly, the WHO has gone so far as to identify NIPAH as a prototype for a future pandemic 42,43 .…”

Pangenomic and immunoinformatics based analysis of Nipah virus revealed CD4+ and CD8+ T-Cell epitopes as potential vaccine candidates

“…Despite the high fatality rates associated with Nipah outbreaks (>70% in Southeast Asia), there are currently no approved medications or vaccines. To avoid uncontrollable situation, it is necessary to develop therapeutic strategy or suitable vaccine to treat NiV (Sen et al, 2019).…”