Potency and metabolic stability: a molecular hybrid case in the design of novel PF74-like small molecules targeting HIV-1 capsid protein

2021 ◽  
Author(s):  
Rajkumar Lalji Sahani ◽  
Thamina Akther ◽  
Maria E. Cilento ◽  
Andres Emanuelli Castaner ◽  
Huanchun Zhang ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Small Molecules ◽  
Capsid Protein ◽  
Metabolic Stability ◽  
Molecular Hybridization ◽  
Hiv 1

To achieve balanced potency and metabolic stability profiles, a molecular hybridization approach was used to design a novel PF74-like chemotype 4. Synthesis, SAR and molecular modeling of chemotype 4 are reported.

scholarly journals Novel PF74-like small molecules targeting the HIV-1 capsid protein: balance of potency and metabolic stability

2020 ◽  
Author(s):  
Lei Wang ◽  
Mary C. Casey ◽  
Sanjeev Kumar V. Vernekar ◽  
Rajkumar Lalji Sahani ◽  
Karen A. Kirby ◽  
...  
Keyword(s):  
Small Molecules ◽  
Capsid Protein ◽  
Metabolic Stability ◽  
Protein Balance ◽  
Hiv 1

scholarly journals Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 452 ◽  
Author(s):  
Sanjeev Kumar V. Vernekar ◽  
Rajkumar Lalji Sahani ◽  
Mary C. Casey ◽  
Jayakanth Kankanala ◽  
Lei Wang ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Small Molecules ◽  
Liver Microsomes ◽  
Binding Mode ◽  
Metabolic Stability ◽  
Analog Synthesis ◽  
Important Host ◽  
Further Development ◽  
Hiv 1 ◽  
Unique Mechanism

HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents an appealing antiviral target. Several CA-targeting small molecules of various chemotypes have been studied, but the peptidomimetic PF74 has drawn particular interest due to its potent antiviral activity, well-characterized binding mode, and unique mechanism of action. Importantly, PF74 competes against important host factors for binding, conferring highly desirable antiviral phenotypes. However, further development of PF74 is hindered by its prohibitively poor metabolic stability, which necessitates the search for structurally novel and metabolically stable chemotypes. We have conducted a pharmacophore-based shape similarity search for compounds mimicking PF74. We report herein the analog synthesis and structure-activity relationship (SAR) of two hits from the search, and a third hit designed via molecular hybridization. All analogs were characterized for their effect on CA hexamer stability, antiviral activity, and cytotoxicity. These assays identified three active compounds that moderately stabilize CA hexamer and inhibit HIV-1. The most potent analog (10) inhibited HIV-1 comparably to PF74 but demonstrated drastically improved metabolic stability in liver microsomes (31 min vs. 0.7 min t1/2). Collectively, the current studies identified a structurally novel and metabolically stable PF74-like chemotype for targeting HIV-1 CA.

scholarly journals Design, Synthesis and Characterization of HIV-1 CA-Targeting Small Molecules: Conformational Restriction of PF74

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 479
Author(s):  
Rajkumar Lalji Sahani ◽  
Raquel Diana-Rivero ◽  
Sanjeev Kumar V. Vernekar ◽  
Lei Wang ◽  
Haijuan Du ◽  
...  
Keyword(s):  
Small Molecules ◽  
Liver Microsomes ◽  
Imidazole Ring ◽  
Metabolic Stability ◽  
Binding Modes ◽  
Conformational Restriction ◽  
Design Synthesis ◽  
Antiviral Activities ◽  
Hiv 1

Small molecules targeting the PF74 binding site of the HIV-1 capsid protein (CA) confer potent and mechanistically unique antiviral activities. Structural modifications of PF74 could further the understanding of ligand binding modes, diversify ligand chemical classes, and allow identification of new variants with balanced antiviral activity and metabolic stability. In the current work, we designed and synthesized three series of PF74-like analogs featuring conformational constraints at the aniline terminus or the phenylalanine carboxamide moiety, and characterized them using a biophysical thermal shift assay (TSA), cell-based antiviral and cytotoxicity assays, and in vitro metabolic stability assays in human and mouse liver microsomes. These studies showed that the two series with the phenylalanine carboxamide moiety replaced by a pyridine or imidazole ring can provide viable hits. Subsequent SAR identified an improved analog 15 which effectively inhibited HIV-1 (EC50 = 0.31 μM), strongly stabilized CA hexamer (ΔTm = 8.7 °C), and exhibited substantially enhanced metabolic stability (t1/2 = 27 min for 15 vs. 0.7 min for PF74). Metabolic profiles from the microsomal stability assay also indicate that blocking the C5 position of the indole ring could lead to increased resistance to oxidative metabolism.

scholarly journals An extensive thermodynamic characterization of the dimerization domain of the HIV-1 capsid protein

2005 ◽  
Vol 14 (9) ◽  
pp. 2387-2404 ◽  
Author(s):  
María C. Lidón-Moya ◽  
Francisco N. Barrera ◽  
Marta Bueno ◽  
Raúl Pérez-Jiménez ◽  
Javier Sancho ◽  
...  
Keyword(s):  
Capsid Protein ◽  
Dimerization Domain ◽  
Thermodynamic Characterization ◽  
Hiv 1

scholarly journals Structure, Function, and Interactions of the HIV-1 Capsid Protein

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 100
Author(s):  
Eric Rossi ◽  
Megan E. Meuser ◽  
Camille J. Cunanan ◽  
Simon Cocklin
Keyword(s):  
Life Cycle ◽  
Capsid Protein ◽  
Adaptor Proteins ◽  
Restriction Factors ◽  
Gag Polyprotein ◽  
Immunodeficiency Virus ◽  
Host Cell Factors ◽  
Hiv 1

The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component of a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields the reverse transcription complex from restriction factors while it enables trafficking to the nucleus by hijacking various adaptor proteins, such as FEZ1 and BICD2. In addition, the capsid facilitates the import and localization of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6. In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein. In the final phase of maturation, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core. The fullerene cone consists of ~250 CA hexamers and 12 CA pentamers and encloses the viral genome and other essential viral proteins for the next round of infection. As research continues to elucidate the role of CA in the HIV-1 life cycle and the importance of the capsid protein becomes more apparent, CA displays potential as a therapeutic target for the development of HIV-1 inhibitors.

scholarly journals Solid-State NMR Studies of HIV-1 Capsid Protein Assemblies

2010 ◽  
Vol 132 (6) ◽  
pp. 1976-1987 ◽  
Author(s):  
Yun Han ◽  
Jinwoo Ahn ◽  
Jason Concel ◽  
In-Ja L. Byeon ◽  
Angela M. Gronenborn ◽  
...  
Keyword(s):  
Solid State ◽  
Capsid Protein ◽  
Solid State Nmr ◽  
Protein Assemblies ◽  
Nmr Studies ◽  
Hiv 1

scholarly journals Site-Specific Structural Variations Accompanying Tubular Assembly of the HIV-1 Capsid Protein

2014 ◽  
Vol 426 (5) ◽  
pp. 1109-1127 ◽  
Author(s):  
Marvin J. Bayro ◽  
Bo Chen ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Capsid Protein ◽  
Structural Variations ◽  
Site Specific ◽  
Hiv 1
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