| Structure-Guided Discovery of ATP-Competitive GRP78 Inhibitors Against Tick-Borne Crimean-Congo Hemorrhagic Fever in Iran |
| Paper ID : 1123-IPCA5 (R1) |
| Authors |
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Fatemeh Shams1, Elina Khanehzar1, Zakkyeh Telmadarraiy2, Faezeh Faghihi3, Amirsajad Jafari *4 11. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran 2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran 21. Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran 2. Rahyan Novin Danesh (RND) University, Sari, Mazandaran, Iran 31. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran 2. Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran 41. Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran |
| Abstract |
| Crimean-Congo Hemorrhagic Fever (CCHF) is a major public health concern in Iran, particularly in endemic regions like Sistan and Baluchestan and Isfahan. The disease is transmitted by various hard (Ixodidae) and soft (Argasidae) ticks, with Hyalomma species (H. marginatum, H. anatolicum, H. asiaticum, H. dromedarii) and Rhipicephalus sanguineus being the primary vectors. Other less common vectors include Dermacentor marginatus, Haemaphysalis sulcata, and the soft tick Ornithodoros lahorensis. The virus is found in 5–15% of Hyalomma ticks in endemic areas, driving sporadic outbreaks. With no approved vaccines or antivirals, CCHF has high mortality rates, prompting the need for innovative treatments. Instead of targeting mutable viral proteins, this study explores a host-directed approach by inhibiting GRP78, a host protein critical for CCHFV entry and replication. Using structure-based drug design, researchers aim to develop ATP-competitive GRP78 inhibitors to disrupt the viral life cycle. Effective CCHF control in Iran requires a combination of tick management, environmental strategies, and novel therapeutics like GRP78-targeting drugs We present a structure-guided, chemically elegant de novo design campaign to develop 10 novel GRP78 inhibitors. Using GRP78’s high-resolution structure (PDB: 6ASY), we sculpted a small-molecule library from the molecular grammar of canonical HSP inhibitors (VER-155008, MKT-077, JG-98, and 17-AAG) but rebuilt each scaffold from the ground up. By reconstructing core pharmacophores through saturation-aware fragment fusion, we optimized drug-likeness, 3D complementarity, and synthetic feasibility characteristics. Virtual screening via AutoDock Vina in PyRx, with VER-155008 as a positive control, revealed exceptional binding scores across the library. SwissADME profiling confirmed balanced ADME properties post-optimization. Among all candidates, the Gelda-Bicyclo hybrid emerged as a standout, surpassing the control with a predicted affinity of –11.4 kcal/mol (vs –8.8 kcal/mol). This compound reimagines the quinone core of 17-AAG with a rigid, sp³-rich bicyclic scaffold, offering enhanced metabolic resilience and precise engagement of the ATP pocket. This study establishes a pioneering antiviral strategy targeting GRP78 to combat tickborne Crimean-Congo Hemorrhagic Fever, with significant implications for Iran, where Hyalomma ticks drive CCHF endemicity. The Gelda-Bicyclo hybrid, with its superior binding affinity, represents a first-in-class candidate for disrupting CCHFV’s reliance on host machinery, offering a mechanistically precise and structurally novel approach. By addressing the urgent need for effective CCHF therapeutics in Iran’s high-risk regions, this work not only advances drug discovery but also lays the foundation for translational medicine to mitigate the devastating impact of tick-borne viral disease |
| Keywords |
| CCHF, De novo drug design, ATP-competitive inhibitors, GRP78, LLM, Docking |
| Status: Abstract Accepted |
