S-1360

The Hantaan virus (HTN) is a member of the hantaviridae family. It is a segmented type, negative-strand virus (sNSVs). It causes hemorrhagic fever with renal syndrome, which includes fever, vascular hemorrhage, and renal failure. This illness is one of the most serious hemorrhagic diseases in the world, and it is a major public health concern due to its high mortality rate. The Hantaan virus RNA-dependent RNA polymerase complex (RdRp) is involved in viral RNA transcription and replication for the survival and transmission of this virus. Therefore, it is a primary target for antiviral drug development. Interference with the endonucleolytic "cap-snatching" reaction by the HTN virus RdRp endonuclease domain is a particularly appealing approach for drug discovery against this virus. This RdRp endonuclease domain of the HTN virus has a metal-dependent catalytic activity. We targeted this metal-dependent enzymatic activity to identify inhibitors that can bind and disrupt this endonuclease enzyme activity using in-silico approaches i.e., molecular docking, molecular dynamics simulation, predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) and drug-likeness studies. The docking studies showed that peramivir, and ingavirin compounds can effectively bind with the manganese ions and engage with other active site residues of this protein. Molecular simulations also showed stable binding of these ligands with the active site of HTN RdRp. Simulation analysis showed that they were in constant contact with the active site manganese ions and amino acid residues of the HTN virus endonuclease domain. This study will help in better understanding the HTN and related viruses.

HIV-1 integrase, a member of a polynucleotidyl transferases superfamily, catalyzes the insertion of the viral DNA into the genome of host cells. It has emerged as a potential target for developing anti-HIV agents. In the last two decades, a number of integrase inhibitors have been developed as potential anti-HIV therapeutics. Several integrase inhibitors have reached later stages of clinical trials including S-1360, L870,810, L870,812 and BMS-707035. Into the bargain, Raltegravir, Elvitegravir and Dolutegravir have been approved by FDA as anti-HIV agents. This review article summarizes the structural insights required for the inhibition of the HIV1 integrase in the context of clinically relevant HIV1 integrase inhibitors. Additionally, the structural features required for overcoming HIV resistance have been discussed. These insights will update the ongoing design of novel antiviral inhibitors.