Fig. 10: Proposed mechanism of action of CJF-III-288. | Nature Communications

Fig. 10: Proposed mechanism of action of CJF-III-288.

From: The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC

Fig. 10

The indane CD4mc, BNM-III-170, in combination with the anti-CoRBS Abs 17b, stabilizes more “open” Env conformations. However, these conformations prevent proper orientation of the Fc region of 17b, impairing efficient interaction with Fc receptors on effector cells and resulting in a low ADCC response both in vitro and in vivo. In contrast, the more potent indoline CD4mc, CJF-III-288, when combined with 17b, stabilizes a more open, asymmetric State-3 Env conformation, enabling 17b to adopt orientations that promote Fc receptor engagement. Env flexibility and the binding of 17b in the context of CJF-III-288 may facilitate Fc receptor engagement on effector cells by accommodating diverse antibody/Env orientations. This mechanism contributes to enhanced ADCC activity in vitro and delays viral rebound following antiretroviral therapy interruption (ATI) in vivo in humanized mice. Cartoons were created in BioRender. Marchitto, L. (2025) https://BioRender.com/rdvwtec.

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