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 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.

The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

2019 ◽  
Vol 19 (18) ◽  
pp. 1650-1675 ◽  
Author(s):  
Damoder Reddy Motati ◽  
Dilipkumar Uredi ◽  
E. Blake Watkins
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Biological Evaluation ◽  
New Drugs ◽  
Design Synthesis ◽  
Mortality And Morbidity ◽  
Glycoprotein Gp120 ◽  
Hiv Entry ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

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

Exposure of the Membrane-Proximal External Region of HIV-1 gp41 in the Course of HIV-1 Envelope Glycoprotein-Mediated Fusion†

Biochemistry ◽  
2007 ◽  
Vol 46 (5) ◽  
pp. 1398-1401 ◽  
Author(s):  
Antony S. Dimitrov ◽  
Amy Jacobs ◽  
Catherine M. Finnegan ◽  
Gabriela Stiegler ◽  
Hermann Katinger ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Hiv 1

scholarly journals Isolation and Characterization of Human Immunodeficiency Virus Type 1 Resistant to the Small-Molecule CCR5 Antagonist TAK-652

2006 ◽  
Vol 51 (2) ◽  
pp. 707-715 ◽  
Author(s):  
Masanori Baba ◽  
Hiroshi Miyake ◽  
Xin Wang ◽  
Mika Okamoto ◽  
Katsunori Takashima
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Small Molecule ◽  
Cross Resistance ◽  
Isolation And Characterization ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT TAK-652, a novel small-molecule chemokine receptor antagonist, is a highly potent and selective inhibitor of CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) replication in vitro. Since TAK-652 is orally bioavailable and has favorable pharmacokinetic profiles in humans, it is considered a promising candidate for an entry inhibitor of HIV-1. To investigate the resistance to TAK-652, peripheral blood mononuclear cells were infected with the R5 HIV-1 primary isolate KK and passaged in the presence of escalating concentrations of the compound for more than 1 year. After 67 weeks of cultivation, the escape virus emerged even in the presence of a high concentration of TAK-652. This virus displayed more than 200,000-fold resistance to TAK-652 compared with the wild type. The escape virus appeared to have cross-resistance to the structurally related compound TAK-779 but retained full susceptibility to TAK-220, which is from a different class of CCR5 antagonists. Furthermore, the escape virus was unable to use CXCR4 as a coreceptor. Analysis for Env amino acid sequences of escape viruses at certain points of passage revealed that amino acid changes accumulated with an increasing number of passages. Several amino acid changes not only in the V3 region but also in other Env regions seemed to be required for R5 HIV-1 to acquire complete resistance to TAK-652.

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 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 Compensatory Substitutions in the HIV-1 Capsid Reduce the Fitness Cost Associated with Resistance to a Capsid-Targeting Small-Molecule Inhibitor

2014 ◽  
Vol 89 (1) ◽  
pp. 208-219 ◽  
Author(s):  
Jiong Shi ◽  
Jing Zhou ◽  
Upul D. Halambage ◽  
Vaibhav B. Shah ◽  
Mallori J. Burse ◽  
...  
Keyword(s):  
Amino Acid ◽  
Small Molecule ◽  
Therapeutic Target ◽  
Binding Pocket ◽  
Host Protein ◽  
Viral Capsid ◽  
Inhibitory Protein ◽  
Hiv 1 ◽  
Ca Protein

ABSTRACTThe HIV-1 capsid plays multiple roles in infection and is an emerging therapeutic target. The small-molecule HIV-1 inhibitor PF-3450074 (PF74) blocks HIV-1 at an early postentry stage by binding the viral capsid and interfering with its function. Selection for resistance resulted in accumulation of five amino acid changes in the viral CA protein, which collectively reduced binding of the compound to HIV-1 particles. In the present study, we dissected the individual and combinatorial contributions of each of the five substitutions Q67H, K70R, H87P, T107N, and L111I to PF74 resistance, PF74 binding, and HIV-1 infectivity. Q67H, K70R, and T107N each conferred low-level resistance to PF74 and collectively conferred strong resistance. The substitutions K70R and L111I impaired HIV-1 infectivity, which was partially restored by the other substitutions at positions 67 and 107. PF74 binding to HIV-1 particles was reduced by the Q67H, K70R, and T107N substitutions, consistent with the location of these positions in the inhibitor-binding pocket. Replication of the 5Mut virus was markedly impaired in cultured macrophages, reminiscent of the previously reported N74D CA mutant. 5Mut substitutions also reduced the binding of the host protein CPSF6 to assembled CA complexesin vitroand permitted infection of cells expressing the inhibitory protein CPSF6-358. Our results demonstrate that strong resistance to PF74 requires accumulation of multiple substitutions in CA to inhibit PF74 binding and compensate for fitness impairments associated with some of the sequence changes.IMPORTANCEThe HIV-1 capsid is an emerging drug target, and several small-molecule compounds have been reported to inhibit HIV-1 infection by targeting the capsid. Here we show that resistance to the capsid-targeting inhibitor PF74 requires multiple amino acid substitutions in the binding pocket of the CA protein. Three changes in CA were necessary to inhibit binding of PF74 while maintaining viral infectivity. Replication of the PF74-resistant HIV-1 mutant was impaired in macrophages, likely owing to altered interactions with host cell factors. Our results suggest that HIV-1 resistance to capsid-targeting inhibitors will be limited by functional constraints on the viral capsid protein. Therefore, this work enhances the attractiveness of the HIV-1 capsid as a therapeutic target.

scholarly journals Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5

2005 ◽  
Vol 49 (11) ◽  
pp. 4708-4715 ◽  
Author(s):  
Masao Nishikawa ◽  
Katsunori Takashima ◽  
Toshiya Nishi ◽  
Rika A. Furuta ◽  
Naoyuki Kanzaki ◽  
...  
Keyword(s):  
Amino Acid ◽  
Small Molecule ◽  
Conformational Changes ◽  
Binding Pocket ◽  
Inhibitory Effect ◽  
Ccr5 Antagonist ◽  
Amino Acid Residues ◽  
Ccr5 Antagonists ◽  
Human Ccr5 ◽  
Hiv 1

ABSTRACT G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.

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