Targeting the Cav1.2-KCa1.1 axis prevents rabies virus internalization and protects against lethal infection
- 1State Key Laboratory of Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China.
- 2National High Containment Laboratory for Animal Disease Control and Prevention, Harbin, People's Republic of China.
- 3Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, People's Republic of China.
Abstract
Rabies is an almost always fatal disease caused by rabies virus (RABV). Once RABV enters the central nervous system, the mortality rate is almost 100%. Therefore, preventing RABV from entering the nervous system is crucial for the development of anti-RABV therapeutics. Here, we found that the L-type calcium channel Cav1.2 pore-forming subunit (Cav1.2) and potassium calcium-activated channel subfamily M alpha 1 (KCa1.1) are involved in the internalization of RABV using an siRNA approach. RABV glycoprotein interacts with Cav1.2, a process that is required for the subsequent activation of the channel. The activated Cav1.2 then interacts with and activates KCa1.1 to regulate the endocytosis of RABV by promoting the F-actin polymerization. Importantly, diltiazem, a blocker of Cav1.2 and an FDA-approved drug, has been shown to substantially reduce mortality in mice infected with RABV. Approximately 70% of mice survived following treatment with diltiazem at 50 mg/kg, whereas the 25 mg/kg dose resulted in 26% survival. Our findings suggest that Cav1.2 is a promising target for the development of antiviral drugs against rabies and enhances our comprehension of the RABV entry mechanism. Author summary: Rabies is a zoonotic infectious disease that is almost invariably fatal once clinical symptoms appear, causing approximately 59,000 deaths annually. While effective post-exposure prophylaxis exists, the expensive cost and chronic global shortage of rabies immunoglobulins leave underserved populations—particularly in rural areas of Asia and Africa—dangerously unprotected. Therefore, discovering affordable, readily accessible therapeutic alternatives to block early viral infection is an urgent global public health need. In this study, we identified that the rabies virus hijacks Cav1.2-KCa1.1 axis to enter cells. By targeting this newly identified axis in the viral entry process, we repurposed diltiazem, a widely used, low-cost, and FDA-approved cardiovascular drug that blocks the Cav1.2 channel. Remarkably, intramuscular administration of diltiazem (50 mg/kg) successfully rescued approximately 70% of mice challenged with a lethal dose of rabies virus. Our findings suggest that repurposed diltiazem shows potential as an early intervention strategy to limit RABV infection. By identifying a safe, mass-produced clinical drug as a potent viral entry inhibitor, this work provides a scalable intervention that could complement existing vaccines and rabies immunoglobulins. This strategy has profound potential to mitigate healthcare inequities in resource-limited regions and significantly advance global efforts to eliminate rabies-related deaths.
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BibTeX
@article{sun2026targeting,
title = {{Targeting the Cav1.2-KCa1.1 axis prevents rabies virus internalization and protects against lethal infection}},
author = {Ziruo Sun and Jinqiu Wang and Zhiyuan Wen and Lei Shuai and Wenjing Sun and Mengjie Yang and Jinyu Wang and Junyu Chen and Tengteng Mi and Xianjing Zhou and Peiran Zhou and Nannan Lv and Zhenbo Zhao and Jinying Ge and Weiye Chen and Xijun Wang and Chong Wang and Zhigao Bu and Jinliang Wang},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014675},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014675},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting the Cav1.2-KCa1.1 axis prevents rabies virus internalization and protects against lethal infection
AU - Ziruo Sun
AU - Jinqiu Wang
AU - Zhiyuan Wen
AU - Lei Shuai
AU - Wenjing Sun
AU - Mengjie Yang
AU - Jinyu Wang
AU - Junyu Chen
AU - Tengteng Mi
AU - Xianjing Zhou
AU - Peiran Zhou
AU - Nannan Lv
AU - Zhenbo Zhao
AU - Jinying Ge
AU - Weiye Chen
AU - Xijun Wang
AU - Chong Wang
AU - Zhigao Bu
AU - Jinliang Wang
PY - 2026
DA - 2026/10/06
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014675
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014675
AB - Rabies is an almost always fatal disease caused by rabies virus (RABV). Once RABV enters the central nervous system, the mortality rate is almost 100%. Therefore, preventing RABV from entering the nervous system is crucial for the development of anti-RABV therapeutics. Here, we found that the L-type calcium channel Cav1.2 pore-forming subunit (Cav1.2) and potassium calcium-activated channel subfamily M alpha 1 (KCa1.1) are involved in the internalization of RABV using an siRNA approach. RABV glycoprotein interacts with Cav1.2, a process that is required for the subsequent activation of the channel. The activated Cav1.2 then interacts with and activates KCa1.1 to regulate the endocytosis of RABV by promoting the F-actin polymerization. Importantly, diltiazem, a blocker of Cav1.2 and an FDA-approved drug, has been shown to substantially reduce mortality in mice infected with RABV. Approximately 70% of mice survived following treatment with diltiazem at 50 mg/kg, whereas the 25 mg/kg dose resulted in 26% survival. Our findings suggest that Cav1.2 is a promising target for the development of antiviral drugs against rabies and enhances our comprehension of the RABV entry mechanism. Author summary: Rabies is a zoonotic infectious disease that is almost invariably fatal once clinical symptoms appear, causing approximately 59,000 deaths annually. While effective post-exposure prophylaxis exists, the expensive cost and chronic global shortage of rabies immunoglobulins leave underserved populations—particularly in rural areas of Asia and Africa—dangerously unprotected. Therefore, discovering affordable, readily accessible therapeutic alternatives to block early viral infection is an urgent global public health need. In this study, we identified that the rabies virus hijacks Cav1.2-KCa1.1 axis to enter cells. By targeting this newly identified axis in the viral entry process, we repurposed diltiazem, a widely used, low-cost, and FDA-approved cardiovascular drug that blocks the Cav1.2 channel. Remarkably, intramuscular administration of diltiazem (50 mg/kg) successfully rescued approximately 70% of mice challenged with a lethal dose of rabies virus. Our findings suggest that repurposed diltiazem shows potential as an early intervention strategy to limit RABV infection. By identifying a safe, mass-produced clinical drug as a potent viral entry inhibitor, this work provides a scalable intervention that could complement existing vaccines and rabies immunoglobulins. This strategy has profound potential to mitigate healthcare inequities in resource-limited regions and significantly advance global efforts to eliminate rabies-related deaths.
SN - 1553-7374
SN - 1553-7366
ER -