A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model
People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment...
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| Published in: | Nature medicine Vol. 25; no. 9; pp. 1377 - 1384 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
New York
Nature Publishing Group US
01-09-2019
Nature Publishing Group |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options
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. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently
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. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.
A new compound that inhibits HIV capsid assembly and nuclear transport functions offers potential as a long-acting antiretroviral. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author Contributions: T.C. conceived the project, with leadership from T.C., J.O.L., S.R.Y. and W.C.T. All authors performed some component of the experiments, with input from J.Z., G.A.P., H.Y., T.C., J.O.L., W.I.S. and A.L.B. Authors W.C.T., J.R.Z., S.D.S., K.C., E.Y.H. and J.O.L. contributed to GS-CA1 design or synthesis. S.R.Y., A.M., D.H., G.J.S., S.A., H.Y. and R.R.R. contributed to antiviral and resistance assays. D.J., N.N. and M.H. contributed to protein production. A.N.-M., G.A.P., S.R.Y. and M.H.W. conducted biophysical studies. A.L. performed protease assays. E.S. performed Western blot studies. J.Z., B.L., E.P., D.G. and S.R.Y. contributed to mouse PK and efficacy studies. J.M.P., W.M.M. and A.L.B. supplied ViewHIV data under contract with Gilead as part of a funded research agreement. All authors contributed to data analysis and interpretation. S.R.Y. wrote the manuscript with contributions from A.M., A.N.-M., G.A.P., E.Y.H. and W.M.M. All authors discussed the results and approved the manuscript. Present address: Vir Biotechnology, Inc., San Francisco, California, USA. |
| ISSN: | 1078-8956 1546-170X |
| DOI: | 10.1038/s41591-019-0560-x |