Pre‐clinical pharmacological profile of QF‐036, a potent HIV‐1 maturation inhibitor

2020 ◽  
Author(s):  
Li Zhao ◽  
Hong‐Hong He ◽  
Ting Ou‐Yang ◽  
Di‐Fa Liu ◽  
Chun‐Hong Jiang ◽  
...  
Keyword(s):  
Pharmacological Profile ◽  
Maturation Inhibitor ◽  
Hiv 1

scholarly journals The HIV-1 maturation inhibitor, EP39, interferes with the dynamic helix-coil equilibrium of the CA-SP1 junction of Gag

2020 ◽  
Vol 204 ◽  
pp. 112634
Author(s):  
Xiaowei Chen ◽  
Pascale Coric ◽  
Valery Larue ◽  
Serge Turcaud ◽  
Xiao Wang ◽  
...  
Keyword(s):  
Maturation Inhibitor ◽  
Hiv 1

scholarly journals Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage

2016 ◽  
Vol 60 (7) ◽  
pp. 3956-3969 ◽  
Author(s):  
Beata Nowicka-Sans ◽  
Tricia Protack ◽  
Zeyu Lin ◽  
Zhufang Li ◽  
Sharon Zhang ◽  
...  
Keyword(s):  
Human Serum ◽  
Second Generation ◽  
Mononuclear Cells ◽  
Integrase Inhibitor ◽  
Wild Type Virus ◽  
Peripheral Blood Mononuclear ◽  
Subtype B ◽  
Maturation Inhibitor ◽  
Hiv 1

ABSTRACTBMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n= 87) ofgag/prrecombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to anin vitromeasurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally,in vitrocombination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potentin vitroanti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat.

scholarly journals In Vitro Resistance to the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PA-457 (Bevirimat)

2006 ◽  
Vol 80 (22) ◽  
pp. 10957-10971 ◽  
Author(s):  
Catherine S. Adamson ◽  
Sherimay D. Ablan ◽  
Ioana Boeras ◽  
Ritu Goila-Gaur ◽  
Ferri Soheilian ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Single Amino Acid ◽  
Compensatory Mutation ◽  
C Terminus ◽  
Immunodeficiency Virus ◽  
Maturation Inhibitor ◽  
Hiv 1

ABSTRACT 3-O-(3′,3′-dimethylsuccinyl)betulinic acid (PA-457 or bevirimat) potently inhibits human immunodeficiency virus type 1 (HIV-1) maturation by blocking a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C terminus of capsid (CA). To gain insights into the mechanism(s) by which HIV-1 could evolve resistance to PA-457 and to evaluate the likelihood of such resistance arising in PA-457-treated patients, we sought to identify and characterize a broad spectrum of HIV-1 variants capable of conferring resistance to this compound. Numerous independent rounds of selection repeatedly identified six single-amino-acid substitutions that independently confer PA-457 resistance: three at or near the C terminus of CA (CA-H226Y, -L231F, and -L231M) and three at the first and third residues of SP1 (SP1-A1V, -A3T, and -A3V). We determined that mutations CA-H226Y, CA-L231F, CA-L231M, and SP1-A1V do not impose a significant replication defect on HIV-1 in culture. In contrast, mutations SP1-A3V and -A3T severely impaired virus replication and inhibited virion core condensation. The replication defect imposed by SP1-A3V was reversed by a second-site compensatory mutation in CA (CA-G225S). Intriguingly, high concentrations of PA-457 enhanced the maturation of SP1 residue 3 mutants. The different phenotypes associated with mutations that confer PA-457 resistance suggest the existence of multiple mechanisms by which HIV-1 can evolve resistance to this maturation inhibitor. These findings have implications for the ongoing development of PA-457 to treat HIV-1 infection in vivo.

scholarly journals Determinants of activity of the HIV-1 maturation inhibitor PA-457

Virology ◽  
2006 ◽  
Vol 356 (1-2) ◽  
pp. 217-224 ◽  
Author(s):  
Feng Li ◽  
Dorian Zoumplis ◽  
Claudia Matallana ◽  
Nicole R. Kilgore ◽  
Mary Reddick ◽  
...  
Keyword(s):  
Maturation Inhibitor ◽  
Hiv 1

scholarly journals Potent Activity of the HIV-1 Maturation Inhibitor Bevirimat in SCID-hu Thy/Liv Mice

PLoS ONE ◽  
2007 ◽  
Vol 2 (11) ◽  
pp. e1251 ◽  
Author(s):  
Cheryl A. Stoddart ◽  
Pheroze Joshi ◽  
Barbara Sloan ◽  
Jennifer C. Bare ◽  
Philip C. Smith ◽  
...  
Keyword(s):  
Maturation Inhibitor ◽  
Hiv 1

scholarly journals The prototype HIV-1 maturation inhibitor, bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles

Retrovirology ◽  
2011 ◽  
Vol 8 (1) ◽  
pp. 101 ◽  
Author(s):  
Albert T Nguyen ◽  
Christa L Feasley ◽  
Ken W Jackson ◽  
Theodore J Nitz ◽  
Karl Salzwedel ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Maturation Inhibitor ◽  
Hiv 1

scholarly journals Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next‐generation HIV‐1 maturation inhibitor

2020 ◽  
Vol 8 (6) ◽  
Author(s):  
Samit R. Joshi ◽  
Disala Fernando ◽  
Stephanie Igwe ◽  
Litza McKenzie ◽  
Anu S. Krishnatry ◽  
...  
Keyword(s):  
Phase I ◽  
Next Generation ◽  
Maturation Inhibitor ◽  
Hiv 1

scholarly journals HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat

Retrovirology ◽  
2011 ◽  
Vol 8 (1) ◽  
pp. 70 ◽  
Author(s):  
Axel Fun ◽  
Noortje M van Maarseveen ◽  
Jana Pokorná ◽  
Renée EM Maas ◽  
Pauline J Schipper ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Maturation Inhibitor ◽  
Hiv 1

scholarly journals Effects of an HIV-1 maturation inhibitor on the structure and dynamics of CA-SP1 junction helices in virus-like particles

2020 ◽  
Vol 117 (19) ◽  
pp. 10286-10293 ◽  
Author(s):  
Sebanti Gupta ◽  
John M. Louis ◽  
Robert Tycko
Keyword(s):  
Chemical Shifts ◽  
Isotopic Labeling ◽  
Relaxation Rates ◽  
Virus Like Particles ◽  
Gag Polyprotein ◽  
Structure And Dynamics ◽  
Maturation Inhibitor ◽  
Rna Maturation ◽  
Segmental Isotopic Labeling ◽  
Hiv 1

HIV-1 maturation involves conversion of the immature Gag polyprotein lattice, which lines the inner surface of the viral membrane, to the mature capsid protein (CA) lattice, which encloses the viral RNA. Maturation inhibitors such as bevirimat (BVM) bind within six-helix bundles, formed by a segment that spans the junction between the CA and spacer peptide 1 (SP1) subunits of Gag, and interfere with cleavage between CA and SP1 catalyzed by the HIV-1 protease (PR). We report solid-state NMR (ssNMR) measurements on spherical virus-like particles (VLPs), facilitated by segmental isotopic labeling, that provide information about effects of BVM on the structure and dynamics of CA–SP1 junction helices in the immature lattice. Although BVM strongly blocks PR-catalyzed CA–SP1 cleavage in VLPs and blocks conversion of VLPs to tubular CA assemblies, 15N and 13C ssNMR chemical shifts of segmentally labeled VLPs with and without BVM are very similar, indicating that interaction with BVM does not alter the six-helix bundle structure appreciably. Only the 15N chemical shift of A280 (the first residue of SP1) changes significantly, consistent with BVM binding to an internal ring of hydrophobic side chains of L279 residues. Measurements of transverse 15N spin relaxation rates reveal a reduction in the amplitudes and/or timescales of backbone N–H bond motions, corresponding to a rigidification of the six-helix bundles. Overall, our data show that inhibition of HIV-1 maturation by BVM involves changes in structure and dynamics that are surprisingly subtle, but still sufficient to produce a large effect on CA–SP1 cleavage.

scholarly journals MicroED structures of HIV-1 Gag CTD-SP1 reveal binding interactions with the maturation inhibitor bevirimat

2018 ◽  
Vol 115 (52) ◽  
pp. 13258-13263 ◽  
Author(s):  
Michael D. Purdy ◽  
Dan Shi ◽  
Jakub Chrustowicz ◽  
Johan Hattne ◽  
Tamir Gonen ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Binding Interactions ◽  
Structure Based Drug Design ◽  
Gag Polyprotein ◽  
Pentacyclic Triterpenoid ◽  
Maturation Inhibitor ◽  
Insight Into ◽  
Hiv 1

HIV-1 protease (PR) cleavage of the Gag polyprotein triggers the assembly of mature, infectious particles. Final cleavage of Gag occurs at the junction helix between the capsid protein CA and the SP1 spacer peptide. Here we used MicroED to delineate the binding interactions of the maturation inhibitor bevirimat (BVM) using very thin frozen-hydrated, 3D microcrystals of a CTD-SP1 Gag construct with and without bound BVM. The 2.9-Å MicroED structure revealed that a single BVM molecule stabilizes the six-helix bundle via both electrostatic interactions with the dimethylsuccinyl moiety and hydrophobic interactions with the pentacyclic triterpenoid ring. These results provide insight into the mechanism of action of BVM and related maturation inhibitors that will inform further drug discovery efforts. This study also demonstrates the capabilities of MicroED for structure-based drug design.

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