Abstract
Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that can cause severe paralytic neurologic disease and immune disorders as well as cancer. An estimated 20 million people worldwide are infected with HTLV-1, with prevalence reaching 30% in some parts of the world. In stark contrast to HIV-1, no direct acting antivirals (DAAs) exist against HTLV-1. The aspartyl protease of HTLV-1 is a dimer similar to that of HIV-1 and processes the viral polyprotein to permit viral maturation. We report that the FDA-approved HIV-1 protease inhibitor darunavir (DRV) inhibits the enzyme with 0.8 μM potency and provides a scaffold for drug design against HTLV-1. Analogs of DRV that we designed and synthesized achieved submicromolar inhibition against HTLV-1 protease and inhibited Gag processing in viral maturation assays and in a chronically HTLV-1 infected cell line. Cocrystal structures of these inhibitors with HTLV-1 protease highlight opportunities for future inhibitor design. Our results show promise toward developing highly potent HTLV-1 protease inhibitors as therapeutic agents against HTLV-1 infections.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 529-538 |
| Number of pages | 10 |
| Journal | ACS Chemical Biology |
| Volume | 16 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 19 2021 |
Bibliographical note
Funding Information:This research was supported by National Institutes of Health grants 1R21AI149716-01A1, P01 GM109767, and R01 GM98550. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DEAC02-06CH11357. GM/CA@APS has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). The Eiger 16M detector was funded by an NIH−Office of Research Infrastructure P r o g r a m s , Hi g h - E n d I n s t r u m e n t a t i o n G r a n t (1S10OD012289-01A1). We thank the beamline specialists at 23-ID-D for their help in data collection. N.T. is supported by NIH fellowship grants T32 DA007097 and F32 AI150351.
Funding Information:
This research was supported by National Institutes of Health grants 1R21AI149716-01A1, P01 GM109767, and R01 GM98550. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. GM/CA@APS has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). The Eiger 16M detector was funded by an NIH–Office of Research Infrastructure Programs, High-End Instrumentation Grant (1S10OD012289-01A1). We thank the beamline specialists at 23-ID-D for their help in data collection. N.T. is supported by NIH fellowship grants T32 DA007097 and F32 AI150351.
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