HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use

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.

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Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor

Molecules ◽

10.3390/molecules24081581 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1581 ◽

Cited By ~ 6

Author(s):

Megan E. Meuser ◽

Adel A. Rashad ◽

Gabriel Ozorowski ◽

Alexej Dick ◽

Andrew B. Ward ◽

...

Keyword(s):

Kinetic Parameter ◽

Small Molecule ◽

Conformational Equilibrium ◽

Therapeutic Modality ◽

Entry Inhibitor ◽

Entry Inhibitors ◽

Antiviral Compounds ◽

Novel Strategy ◽

Positive Effect ◽

Hiv 1

Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts.

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Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2015.11.006 ◽

2015 ◽

Vol 23 (24) ◽

pp. 7618-7628 ◽

Cited By ~ 5

Author(s):

Francesca Curreli ◽

Kashfia Haque ◽

Lihua Xie ◽

Qian Qiu ◽

Jinfeng Xu ◽

...

Keyword(s):

Antiviral Activity ◽

Small Molecule ◽

Entry Inhibitor ◽

Hiv 1

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Structure of BMS-806, a Small-molecule HIV-1 Entry Inhibitor, Bound to BG505 SOSIP.664 HIV-1 Env Trimer

AIDS Research and Human Retroviruses ◽

10.1089/aid.2014.5307c.abstract ◽

2014 ◽

Vol 30 (S1) ◽

pp. A151-A151 ◽

Cited By ~ 2

Author(s):

Marie Pancera ◽

Aliaksandr Druz ◽

Tongqing Zhou ◽

Sijy O'Dell ◽

Mark Louder ◽

...

Keyword(s):

Small Molecule ◽

Entry Inhibitor ◽

Hiv 1

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

10.26434/chemrxiv.8966363.v1 ◽

2019 ◽

Author(s):

Althea Gaffney ◽

Aakansha Nangarlia ◽

Steven Gossert ◽

Adel A. Rashad ◽

Alamgir Hossain ◽

...

Keyword(s):

Amino Acid ◽

Small Molecule ◽

Envelope Glycoprotein ◽

Entry Inhibitor ◽

External Region ◽

Design Synthesis ◽

Dual Action ◽

Functional Components ◽

Amino Acid Segment ◽

Hiv 1

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.

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Direct Inactivation of Human Immunodeficiency Virus Type 1 by a Novel Small-Molecule Entry Inhibitor, DCM205

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01001-06 ◽

2007 ◽

Vol 51 (5) ◽

pp. 1780-1786 ◽

Cited By ~ 6

Author(s):

Yen T. Duong ◽

D. Christopher Meadows ◽

Indresh K. Srivastava ◽

Jacquelyn Gervay-Hague ◽

Thomas W. North

Keyword(s):

Human Immunodeficiency Virus ◽

Small Molecule ◽

Sexual Transmission ◽

Entry Inhibitor ◽

Molecule Inhibitor ◽

Cellular Target ◽

Immunodeficiency Virus ◽

Hiv Entry ◽

Hiv 1

ABSTRACT With more than 40 million people living with human immunodeficiency virus (HIV), there is an urgent need to develop drugs that can be used in the form of a topical microbicide to prevent infection through sexual transmission. DCM205 is a recently discovered small-molecule inhibitor of HIV type 1 (HIV-1) that is able to directly inactivate HIV-1 in the absence of a cellular target. DCM205 is active against CXCR4-, CCR5-, and dual-tropic laboratory-adapted and primary strains of HIV-1. DCM205 binds to the HIV-1 envelope glycoprotein, and competition studies map the DCM205 binding at or near the V3 loop of gp120. Binding to this site interferes with the soluble CD4 interaction. With its ability to disable the virus particle, DCM205 represents a promising new class of HIV entry inhibitor that can be used as a strategy in the prevention of HIV-1/AIDS.

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Antigenicity and Immunogenicity of HIV-1 Envelope Trimers Complexed to a Small-Molecule Viral Entry Inhibitor

Journal of Virology ◽

10.1128/jvi.00958-20 ◽

2020 ◽

Vol 94 (21) ◽

Author(s):

S. Munir Alam ◽

Kenneth Cronin ◽

Robert Parks ◽

Kara Anasti ◽

Haitao Ding ◽

...

Keyword(s):

Small Molecule ◽

Viral Entry ◽

Neutralizing Antibodies ◽

Conformational Transition ◽

Rhesus Macaques ◽

Entry Inhibitor ◽

Tier 2 ◽

Membrane Bound ◽

High Mannose ◽

Hiv 1

ABSTRACT Small-molecule viral entry inhibitors, such as BMS-626529 (BMS-529), allosterically block CD4 binding to HIV-1 envelope (Env) and inhibit CD4-induced structural changes in Env trimers. Here, we show that the binding of BMS-529 to clade C soluble chimeric gp140 SOSIP (ch.SOSIP) and membrane-bound trimers with intact transmembrane domain (gp150) prevented trimer conformational transitions and enhanced their immunogenicity. When complexed to BMS-529, ch.SOSIP trimers retained their binding to broadly neutralizing antibodies (bNAbs) and to their unmutated common ancestor (UCA) antibodies, while exposure of CD4-induced (CD4i) non-bNAb epitopes was inhibited. BMS-529-complexed gp150 trimers in detergent micelles, which were isolated from CHO cells, bound to bNAbs, including UCA and intermediates of the CD4 binding site (bs) CH103 bNAb lineage, and showed limited exposure of CD4i epitopes and a glycosylation pattern with a preponderance of high-mannose glycans. In rabbits, BMS-529-complexed V3 glycan-targeting ch.SOSIP immunogen induced in the majority of immunized animals higher neutralization titers against both autologous and select high mannose-bearing heterologous tier 2 pseudoviruses than those immunized with the noncomplexed ch.SOSIP. In rhesus macaques, BMS-529 complexed to CD4 bs-targeting ch.SOSIP immunogen induced stronger neutralization against tier 2 pseudoviruses bearing high-mannose glycans than noncomplexed ch.SOSIP trimer immunogen. When immunized with gp150 complexed to BMS-529, rhesus macaques showed neutralization against tier 2 pseudoviruses with targeted glycan deletion and high-mannose glycan enrichment. These results demonstrated that stabilization of Env trimer conformation with BMS-529 improved the immunogenicity of select chimeric SOSIP trimers and elicited tier 2 neutralizing antibodies of higher potency than noncomplexed trimers. IMPORTANCE Soluble forms of HIV-1 envelope trimers exhibit conformational heterogeneity and undergo CD4-induced (CD4i) exposure of epitopes of non-neutralizing antibodies that can potentially hinder induction of broad neutralizing antibody responses. These limitations have been mitigated through recent structure-guided approaches and include trimer-stabilizing mutations that resist trimer conformational transition and exposure of CD4i epitopes. The use of small-molecule viral inhibitors that allosterically block CD4 binding represents an alternative strategy for stabilizing Env trimer in the pre-CD4-triggered state of both soluble and membrane-bound trimers. In this study, we report that the viral entry inhibitor BMS-626529 restricts trimer conformational transition and improves the immunogenicity of select Env trimer immunogens.

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