Since their identification in the 1950s, hantaviruses have remained a persistent neglected disease in the medical field. While the hemorrhagic fever with renal syndrome (HFRS)—causing Old World hantaviruses (i.e. HTNV, Puumala virus) maintain case fatality rates (CFRs) up to 15%, the hantavirus pulmonary syndrome (HPS)—causing New World hantaviruses frequently emerge with CFRs up to 40%, making the latter particularly concerning for the medical and global health surveillance communities alike. Compounding the aforementioned notoriety is the lack of FDA approved/disease-specific treatment for hantavirus infections across Old and New World strains. Following in the discovery of β3 integrins as crucial gateways for pathogenic hantavirus replication—with αIIβ3 serving as the primary receptor for Old World pathogenic hantaviruses, and correspondingly αvβ3 in New World strains thereof—a novel strategy was devised in the late 2000s to inhibit the aforementioned integrin receptor instead of the progenitor virions themselves. Namely, cyclic pentapeptide inhibitors of αvβ3 (i.e. cyclo-[CPFVC]), further expanded to include more potent peptidomimetics, were discovered to inhibit the replication of various hantavirus strains, such as Sin Nombre virus (SNV), New York virus-1 (NY-V1), and Andes virus (ANDV). G319-0078, a ligand-based virtual screening (LBVS) peptidomimetic hit with a 100-fold increased potency compared to cyclo-[CPFVC], was found to be the most promising candidate molecule for hantavirus inhibition, and thus served as the template ligand for this study aimed at expanding and identifying five lead ligands in silico. Following initial molecular docking of a panel of 39 (L2-40) structural analogues of G319-0078, five lead compounds with optimized docking scores and cyclized scaffolds bearing a cyclophosphinamide group were identified as binding to the orthosteric binding site of G319-0078 at the β3 subunit of αvβ3: X47-A, X47-B, X47-C, X47-D, and X47-E. Further molecular dynamics simulation (MDsim—RMSD, RMSF, SASA), normal mode/dynamic cross-correlation matrix (NMA/DCCM), and ADME-Tox analyses collectively prioritized X47-C as the most promising in silico lead compound, revealing a theoretical hantavirus treatment strategy necessitating future empirical confirmation in vitro and in vivo.
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