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

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1581 ◽  
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.

scholarly journals Design, Synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors

2021 ◽  
pp. 116000
Author(s):  
Francesca Curreli ◽  
Shahad Ahmed ◽  
Sofia M. Benedict Victor ◽  
Ildar R. Iusupov ◽  
Evgeny A. Spiridonov ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Small Molecule ◽  
Design Synthesis ◽  
Entry Inhibitors ◽  
Hiv 1

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

2002 ◽  
Vol 99 (1) ◽  
pp. 395-400 ◽  
Author(s):  
A. Trkola ◽  
S. E. Kuhmann ◽  
J. M. Strizki ◽  
E. Maxwell ◽  
T. Ketas ◽  
...  
Keyword(s):  
Small Molecule ◽  
Entry Inhibitor ◽  
Hiv 1

scholarly journals Discovery and optimization of novel small-molecule HIV-1 entry inhibitors using field-based virtual screening and bioisosteric replacement

2014 ◽  
Vol 24 (23) ◽  
pp. 5439-5445 ◽  
Author(s):  
Marina Tuyishime ◽  
Matt Danish ◽  
Amy Princiotto ◽  
Marie K. Mankowski ◽  
Rae Lawrence ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Small Molecule ◽  
Entry Inhibitors ◽  
Bioisosteric Replacement ◽  
Hiv 1

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

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.

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

2015 ◽  
Vol 23 (24) ◽  
pp. 7618-7628 ◽  
Author(s):  
Francesca Curreli ◽  
Kashfia Haque ◽  
Lihua Xie ◽  
Qian Qiu ◽  
Jinfeng Xu ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Small Molecule ◽  
Entry Inhibitor ◽  
Hiv 1

scholarly journals Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity

2016 ◽  
Vol 24 (22) ◽  
pp. 5988-6003 ◽  
Author(s):  
Francesca Curreli ◽  
Dmitry S. Belov ◽  
Ranjith R. Ramesh ◽  
Naisargi Patel ◽  
Andrea Altieri ◽  
...  
Keyword(s):  
Small Molecule ◽  
Broad Spectrum ◽  
Design Synthesis ◽  
Entry Inhibitors ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1430
Author(s):  
Rama Karadsheh ◽  
Megan E. Meuser ◽  
Simon Cocklin
Keyword(s):  
Short Communication ◽  
Human Liver Microsome ◽  
Core Region ◽  
Metabolic Stability ◽  
Entry Inhibitor ◽  
Entry Inhibitors ◽  
The Core ◽  
The Stability ◽  
Hiv 1

Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal—to design an entry inhibitor with improved drug-like qualities—and warrants expanded studies to achieve this.

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

2014 ◽  
Vol 30 (S1) ◽  
pp. A151-A151 ◽  
Author(s):  
Marie Pancera ◽  
Aliaksandr Druz ◽  
Tongqing Zhou ◽  
Sijy O'Dell ◽  
Mark Louder ◽  
...  
Keyword(s):  
Small Molecule ◽  
Entry Inhibitor ◽  
Hiv 1

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

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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