Advantages
- High reactivation and selective apoptosis induction ability against latent HIV-infected cells.
- Complete elimination of HIV latently infected cells in combination with existing anti-HIV drugs.
- That compounds can be synthesized in large quantities.
Background and Technology
Combination chemotherapy for human immunodeficiency virus (HIV) infection, including reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors (cART), has been successful in suppressing the onset of acquired immunodeficiency syndrome (AIDS). However, latent infected cells (reservoir cells), in which HIV DNA is incorporated into the genome, cannot be eliminated from the patient’s body, and if cART is interrupted, HIV may begin to proliferate again and AIDS may develop. Therefore, patients must remain on cART for the rest of their lives, which raises issues of side effects and cost.
The “Shock and Kill” approach, in which reservoir cells are reactivated by Latency-Reversing Agents (LRAs) and then killed by anti-HIV drugs, has been reported as a strategy for eliminating reservoir cells. Histone deacetylase inhibitors, protein kinase C activators, and other agents have been known as LRAs, but none have been approved.
We screened LRAs with favorable properties over existing LRAs from Kumamoto University’s natural product library and confirmed their efficacy in vitro and in vivo.
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Reference and Patent
- Patent application: WO2022/186391
Principal Investigator
Shogo MISUMI, Professor (Kumamoto University Graduate School of Pharmaceutical Sciences)
Current Stage and Next Step
- We have confirmed that the developed compound C2 causes reservoir cells to disappear by apoptosis in vitro, and in combination with the anti-HIV agent CX, the virus does not appear in the culture supernatant after discontinuation of CX administration (more effective than PEP005 of the existing LAR) (upper figure). In an in vivo reservoir cell activation evaluation model, it was confirmed that the cells can indeed be activated and that the effect is enhanced when combined with the BRD inhibitor JQ1 (below figure).
- Development compound C2 has been suggested to fragment the viral genome of reservoir cells in a non-infective manner. Pharmacokinetic and primate model experiments are planned and we are seeking collaborative partner companies.
Project No. BK-04535