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Article ; Online: Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability.

Mulato, Andrew / Lansdon, Eric / Aoyama, Ron / Voigt, Johannes / Lee, Michael / Liclican, Albert / Lee, Gary / Singer, Eric / Stafford, Brian / Gong, Ruoyu / Murray, Bernard / Chan, Julie / Lee, Johnny / Xu, Yili / Ahmadyar, Shekeba / Gonzalez, Ana / Cho, Aesop / Stepan, George J / Schmitz, Uli /

Schultz, Brian / Marchand, Bruno / Brumshtein, Boris / Wang, Ruth / Yu, Helen / Cihlar, Tomas / Xu, Lianhong / Yant, Stephen R

Antimicrobial agents and chemotherapy

2024 Volume 68, Issue 4, Page(s) e0137323

Abstract: Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and ... ...

Abstract	Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no
MeSH term(s)	Humans ; HIV Protease Inhibitors/pharmacology ; HIV Protease Inhibitors/therapeutic use ; Darunavir/pharmacology ; Darunavir/therapeutic use ; Atazanavir Sulfate/pharmacology ; Atazanavir Sulfate/therapeutic use ; Drug Resistance, Viral ; HIV-1/genetics ; Anti-Retroviral Agents/therapeutic use ; HIV Infections/drug therapy ; HIV Protease/genetics ; HIV Protease/metabolism
Chemical Substances	HIV Protease Inhibitors ; Darunavir (YO603Y8113) ; Atazanavir Sulfate (4MT4VIE29P) ; Anti-Retroviral Agents ; HIV Protease (EC 3.4.23.-)
Language	English
Publishing date	2024-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.01373-23
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Article ; Online: Nucleotide Prodrug Containing a Nonproteinogenic Amino Acid To Improve Oral Delivery of a Hepatitis C Virus Treatment.

Feng, Joy Y / Wang, Ting / Park, Yeojin / Babusis, Darius / Birkus, Gabriel / Xu, Yili / Voitenleitner, Christian / Fenaux, Martijn / Yang, Huiling / Eng, Stacey / Tirunagari, Neeraj / Kirschberg, Thorsten / Cho, Aesop / Ray, Adrian S

Antimicrobial agents and chemotherapy

2018 Volume 62, Issue 8

Abstract: Delivery of pharmacologically active nucleoside triphosphate analogs to sites of viral infection is challenging. In prior work we identified a 2'- ...

Abstract	Delivery of pharmacologically active nucleoside triphosphate analogs to sites of viral infection is challenging. In prior work we identified a 2'-
MeSH term(s)	Administration, Oral ; Animals ; Antiviral Agents/administration & dosage ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/therapeutic use ; Caco-2 Cells ; Cells, Cultured ; Dogs ; Hepacivirus/drug effects ; Hepacivirus/pathogenicity ; Hepatitis C/virology ; Humans ; Male ; Nucleotides/administration & dosage ; Nucleotides/pharmacokinetics ; Nucleotides/therapeutic use ; Prodrugs/administration & dosage ; Prodrugs/pharmacokinetics ; Prodrugs/therapeutic use ; Rats ; Triazines/administration & dosage ; Triazines/pharmacokinetics ; Triazines/therapeutic use ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Nucleotides ; Prodrugs ; Triazines ; GS-6620 (WD5DUG7X38)
Language	English
Publishing date	2018-07-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.00620-18
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Article: Practical synthesis of 1′-substituted Tubercidin C-nucleoside analogs

Metobo, Sammy E / Xu, Jie / Saunders, Oliver L / Butler, Thomas / Aktoudianakis, Evangelos / Cho, Aesop / Kim, Choung U

Tetrahedron letters. 2012 Feb. 1, v. 53, no. 5

2012

Abstract: Several 1′-substituted analogs of Tubercidin C-nucleosides were prepared using a highly convergent synthesis. Good to high diastereoselectivity was achieved using a variety of nucleophiles targeting the 1′-position. The source for this stereoselectivity ... ...

Abstract	Several 1′-substituted analogs of Tubercidin C-nucleosides were prepared using a highly convergent synthesis. Good to high diastereoselectivity was achieved using a variety of nucleophiles targeting the 1′-position. The source for this stereoselectivity is herein proposed. It is thought to be attributed to a temperature-dependent chelation of the incoming nucleophile to either the 2′- or 3′-benzyloxy ether of the ribose core.
Keywords	chelation ; chemical structure ; organic compounds ; ribose ; synthesis
Language	English
Dates of publication	2012-0201
Size	p. 484-486.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	204287-3
ISSN	1873-3581 ; 0040-4039
ISSN (online)	1873-3581
ISSN	0040-4039
DOI	10.1016/j.tetlet.2011.11.055
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Article ; Online: Synthesis and characterization of 1'-C-cyano-2'-fluoro-2'-C-methyl pyrimidine nucleosides as HCV polymerase inhibitors.

Kirschberg, Thorsten A / Mish, Michael R / Zhang, Lijun / Squires, Neil H / Wang, Ke-Yu / Cho, Aesop / Feng, Joy Y / Fenaux, Martijn / Babusis, Darius / Park, Yeojin / Ray, Adrian S / Kim, Choung U

Bioorganic & medicinal chemistry letters

2015 Volume 25, Issue 5, Page(s) 1040–1043

Abstract: The first synthesis of 1'-C-CN, 2'-F, 2'-C-Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1'-C-CN, 2'-C-Me as well as the 2'-F, 2'-C-Me pyrimidines. A phosphoramidate prodrug of the cytidine derivative showed activity in ... ...

Abstract	The first synthesis of 1'-C-CN, 2'-F, 2'-C-Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1'-C-CN, 2'-C-Me as well as the 2'-F, 2'-C-Me pyrimidines. A phosphoramidate prodrug of the cytidine derivative showed activity in the low micromolar range against HCV replicons.
MeSH term(s)	Amides/chemistry ; Amides/pharmacology ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Cell Line ; Halogenation ; Hepacivirus/drug effects ; Hepacivirus/enzymology ; Hepatitis C/drug therapy ; Hepatitis C/virology ; Humans ; Methylation ; Phosphoric Acids/chemistry ; Phosphoric Acids/pharmacology ; Prodrugs/chemistry ; Prodrugs/pharmacology ; Pyrimidine Nucleosides/chemistry ; Pyrimidine Nucleosides/pharmacology ; RNA Replicase/antagonists & inhibitors ; Replicon/drug effects
Chemical Substances	Amides ; Antiviral Agents ; Phosphoric Acids ; Prodrugs ; Pyrimidine Nucleosides ; phosphoramidic acid (9Q189608GB) ; RNA Replicase (EC 2.7.7.48)
Language	English
Publishing date	2015-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2015.01.021
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Article ; Online: Synthesis of 1'-C-cyano pyrimidine nucleosides and characterization as HCV polymerase inhibitors.

Kirschberg, Thorsten A / Mish, Michael / Squires, Neil H / Zonte, Sebastian / Aktoudianakis, Evangelos / Metobo, Sammy / Butler, Thomas / Ju, Xie / Cho, Aesop / Ray, Adrian S / Kim, Choung U

Nucleosides, nucleotides & nucleic acids

2015 Volume 34, Issue 11, Page(s) 763–785

Abstract: Ribose modified 1'-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and ... ...

Abstract	Ribose modified 1'-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity.
MeSH term(s)	Chemistry Techniques, Synthetic ; DNA-Directed RNA Polymerases/antagonists & inhibitors ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Hepacivirus/enzymology ; Pyrimidine Nucleosides/chemical synthesis ; Pyrimidine Nucleosides/chemistry ; Pyrimidine Nucleosides/pharmacology
Chemical Substances	Enzyme Inhibitors ; Pyrimidine Nucleosides ; DNA-Directed RNA Polymerases (EC 2.7.7.6)
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article
ZDB-ID	2008956-9
ISSN	1532-2335 ; 1525-7770
ISSN (online)	1532-2335
ISSN	1525-7770
DOI	10.1080/15257770.2015.1075550
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Article: Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nucleosides

Cho, Aesop / Saunders, Oliver L / Butler, Thomas / Zhang, Lijun / Xu, Jie / Vela, Jennifer E / Feng, Joy Y / Ray, Adrian S / Kim, Choung U

Bioorganic & medicinal chemistry letters. 2012 Apr. 15, v. 22, no. 8

2012

Abstract: A series of 1′-substituted analogs of 4-aza-7,9-dideazaadenosine C-nucleoside were prepared and evaluated for the potential as antiviral agents. These compounds showed a broad range of inhibitory activity against various RNA viruses. In particular, the ... ...

Abstract	A series of 1′-substituted analogs of 4-aza-7,9-dideazaadenosine C-nucleoside were prepared and evaluated for the potential as antiviral agents. These compounds showed a broad range of inhibitory activity against various RNA viruses. In particular, the whole cell potency against HCV when R=CN was attributed to inhibition of HCV NS5B polymerase and intracellular concentration of the corresponding nucleoside triphosphate.
Keywords	RNA ; antiviral agents ; antiviral properties ; chemistry ; nucleoside-triphosphate phosphatase ; viruses ; covid19
Language	English
Dates of publication	2012-0415
Size	p. 2705-2707.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2012.02.105
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Article: Synthesis of 1-amino-2-vinylcyclopropane-1-phosphinates. Conversion of a phosphonate to phosphinates

Pyun, Hyung-Jung / Clarke, Michael O / Cho, Aesop / Casarez, Anthony / Ji, Mingzhe / Fardis, Maria / Pastor, Richard / Sheng, X. Christopher / Kim, Choung U

Tetrahedron letters. 2012 May 2, v. 53, no. 18

2012

Abstract: Conversion of diethyl 1-amino-2-vinylcyclopropanephosphonate to ethyl 1-amino-2-vinylcyclopropanephosphinate was accomplished by using either nucleophilic or electrophilic carbon reagents. Hydrolysis of the phosphonate diethyl ester to the mono acid ... ...

Abstract	Conversion of diethyl 1-amino-2-vinylcyclopropanephosphonate to ethyl 1-amino-2-vinylcyclopropanephosphinate was accomplished by using either nucleophilic or electrophilic carbon reagents. Hydrolysis of the phosphonate diethyl ester to the mono acid followed by oxalyl chloride treatment provided the phosphonomonochloridate, which was treated with nucleophilic organometallic agents to afford phosphinate ethyl esters. Alternatively, the chloridate was reduced to the phosphonous ethyl ester, and then alkylated with various electrophilic alkylating agents to obtain phosphinate ethyl esters.
Keywords	carbon ; chemical structure ; esters ; hydrolysis ; synthesis
Language	English
Dates of publication	2012-0502
Size	p. 2360-2363.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	204287-3
ISSN	1873-3581 ; 0040-4039
ISSN (online)	1873-3581
ISSN	0040-4039
DOI	10.1016/j.tetlet.2012.02.111
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Article ; Online: Preparation and biological evaluation of 1'-cyano-2'-C-methyl pyrimidine nucleosides as HCV NS5B polymerase inhibitors.

Mish, Michael R / Cho, Aesop / Kirschberg, Thorsten / Xu, Jie / Zonte, C Sebastian / Fenaux, Martijn / Park, Yeojin / Babusis, Darius / Feng, Joy Y / Ray, Adrian S / Kim, Choung U

Bioorganic & medicinal chemistry letters

2014 Volume 24, Issue 14, Page(s) 3092–3095

Abstract: The first synthesis of 1'-cyano-2'-C-methyl pyrimidine nucleosides is described. Anti-HCV activity of these nucleosides and their nucleotide phosphoramidate prodrugs was assessed and compared to the 1'-unsubstituted counterparts and to the related 1'- ... ...

Abstract	The first synthesis of 1'-cyano-2'-C-methyl pyrimidine nucleosides is described. Anti-HCV activity of these nucleosides and their nucleotide phosphoramidate prodrugs was assessed and compared to the 1'-unsubstituted counterparts and to the related 1'-cyano-2'-C-methyl C-nucleoside parent of GS-6620.
MeSH term(s)	Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Hepacivirus/drug effects ; Hepacivirus/enzymology ; Microbial Sensitivity Tests ; Molecular Conformation ; Nucleosides/chemical synthesis ; Nucleosides/chemistry ; Nucleosides/pharmacology ; Pyrimidine Nucleosides/chemical synthesis ; Pyrimidine Nucleosides/chemistry ; Pyrimidine Nucleosides/pharmacology ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; RNA-Dependent RNA Polymerase/metabolism ; Structure-Activity Relationship ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Enzyme Inhibitors ; Nucleosides ; Pyrimidine Nucleosides ; Viral Nonstructural Proteins ; NS-5 protein, hepatitis C virus (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2014-05-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2014.05.015
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Article ; Online: Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase.

Appleby, Todd C / Perry, Jason K / Murakami, Eisuke / Barauskas, Ona / Feng, Joy / Cho, Aesop / Fox, David / Wetmore, Diana R / McGrath, Mary E / Ray, Adrian S / Sofia, Michael J / Swaminathan, S / Edwards, Thomas E

Science (New York, N.Y.)

2014 Volume 347, Issue 6223, Page(s) 771–775

Abstract: Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA ... ...

Abstract	Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by determining crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our analysis revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A β loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clinically active metabolite formed by sofosbuvir, to elucidate key molecular interactions in the active site.
MeSH term(s)	Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; Hepacivirus/enzymology ; Hepacivirus/genetics ; Hepacivirus/physiology ; Molecular Sequence Data ; Protein Structure, Secondary ; RNA, Viral/biosynthesis ; RNA-Dependent RNA Polymerase/chemistry ; Ribonucleotides/chemistry ; Sofosbuvir ; Uridine Monophosphate/analogs & derivatives ; Uridine Monophosphate/chemistry ; Viral Nonstructural Proteins/chemistry ; Virus Replication
Chemical Substances	RNA, Viral ; Ribonucleotides ; Viral Nonstructural Proteins ; Uridine Monophosphate (E2OU15WN0N) ; NS-5 protein, hepatitis C virus (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Sofosbuvir (WJ6CA3ZU8B)
Language	English
Publishing date	2014-11-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1259210
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Article ; Online: Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620.

Murakami, Eisuke / Wang, Ting / Babusis, Darius / Lepist, Eve-Irene / Sauer, Dorothea / Park, Yeojin / Vela, Jennifer E / Shih, Robert / Birkus, Gabriel / Stefanidis, Dimitrios / Kim, Choung U / Cho, Aesop / Ray, Adrian S

Antimicrobial agents and chemotherapy

2014 Volume 58, Issue 4, Page(s) 1943–1951

Abstract: The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-isopropyl ester and phenol moieties attached to the 5'-phosphate that release the nucleoside monophosphate in hepatocytes and a 3'-isobutyryl ester ... ...

Abstract	The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-isopropyl ester and phenol moieties attached to the 5'-phosphate that release the nucleoside monophosphate in hepatocytes and a 3'-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3'-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.
MeSH term(s)	Administration, Oral ; Animals ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Caco-2 Cells ; Cell Line ; Cricetinae ; Dogs ; Hepacivirus/drug effects ; Humans ; Macaca fascicularis ; Male ; Mesocricetus ; Prodrugs/pharmacokinetics ; Prodrugs/pharmacology
Chemical Substances	Antiviral Agents ; Prodrugs
Language	English
Publishing date	2014-01-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.02350-13
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