ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
2 files

Irreversible HIV-1 Inactivation Employing a Small Molecule Dual-Action Virolytic Entry Inhibitor Strategy

preprint
submitted on 19.07.2019, 17:04 and posted on 23.07.2019, 16:31 by Althea Gaffney, Aakansha Nangarlia, Steven Gossert, Adel A. Rashad, Alamgir Hossain, Cameron Abrams, Amos B. Smith III, Irwin M. Chaiken
The design, synthesis and validation of a family of small molecule “Dual-Action Virucidal EntryInhibitors” (DAVEIs) has been achieved that result in irreversible lytic inactivation of HIV-1 virions. These constructs contained two functional components that endow the capacity to bindsimultaneously to both the gp120 and gp41 subunits of the HIV-1 Envelope glycoprotein (Env). One component is derived from BNM-III-170, a small molecule CD4 mimic warhead that binds togp120. The second component, a Trp3 peptide, is a 9-amino acid segment based on the gp41 Membrane Proximal External Region (MPER) that has been proposed to bind to the gp41 MPERdomain of the Env. The resulting smDAVEIs both inhibit infection with low micromolar potency and induce lysis of the HIV-1 virion. The lytic activity was selective for functional HIV-1 virions. Crucially, virolysis was found to be dependent on covalent tethering of the BNM-III-170 and Trp3 domains with various spacers, as coadministration of the un-crosslinked components proved not to be lytic. Computational modeling supports a mechanism in which DAVEIs bind to open-state Env trimers and induce relative motion of gp120 subunits that further opens the trimers. Overall, this work represents a promising new step toward the use of small-molecule DAVEIs for eradication of HIV.

Funding

GM115249 GM56550 AI150471

History

Email Address of Submitting Author

cfa22@drexel.edu

Institution

Drexel University

Country

USA

ORCID For Submitting Author

0000-0002-1240-0816

Declaration of Conflict of Interest

None.

Exports

Logo branding

Exports