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Article ; Online: Biology of the hepatitis B virus (HBV) core and capsid assembly modulators (CAMs) for chronic hepatitis B (CHB) cure.

McFadden, William M / Sarafianos, Stefan G

2023 Volume 5, Issue 4, Page(s) 199–207

Abstract: Hepatitis B virus (HBV) is a hepadnavirus, a small DNA virus that infects liver tissue, with some unusual replication steps that share similarities to retroviruses. HBV infection can lead to chronic hepatitis B (CHB), a life-long infection associated ... ...

Abstract	Hepatitis B virus (HBV) is a hepadnavirus, a small DNA virus that infects liver tissue, with some unusual replication steps that share similarities to retroviruses. HBV infection can lead to chronic hepatitis B (CHB), a life-long infection associated with significant risks of liver disease, especially if untreated. HBV is a significant global health problem, with hundreds of millions currently living with CHB. Currently approved strategies to prevent or inhibit HBV are highly effective, however, a cure for CHB has remained elusive. To achieve a cure, elimination of the functionally integrated HBV covalently closed chromosomal DNA (cccDNA) genome is required. The capsid core is an essential component of HBV replication, serving roles when establishing infection and in creating new virions. Over the last two and a half decades, significant efforts have been made to find and characterize antivirals that target the capsid, specifically the HBV core protein (Cp). The antivirals that interfere with the kinetics and morphology of the capsid, termed capsid assembly modulators (CAMs), are extremely potent, and clinical investigations indicate they are well tolerated and highly effective. Several CAMs offer the potential to cure CHB by decreasing the cccDNA pools. Here, we review the biology of the HBV capsid, focused on Cp, and the development of inhibitors that target it.
Language	English
Publishing date	2023-08-01
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	3140544-7
ISSN	2434-9194 ; 2434-9194 ; 2434-9186
ISSN (online)	2434-9194
ISSN	2434-9194 ; 2434-9186
DOI	10.35772/ghm.2023.01065
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeting the HIV-1 and HBV Capsids, an EnCore.

McFadden, William M / Sarafianos, Stefan G

Viruses

2023 Volume 15, Issue 4

Abstract: Not many structures are common among all viruses: only nucleic acid and a protein coat [ ... ]. ...

Abstract	Not many structures are common among all viruses: only nucleic acid and a protein coat [...].
MeSH term(s)	Capsid/metabolism ; HIV-1/metabolism ; Hepatitis B virus/metabolism ; Capsid Proteins/metabolism ; Lactic Acid/analysis
Chemical Substances	Capsid Proteins ; Lactic Acid (33X04XA5AT)
Language	English
Publishing date	2023-03-31
Publishing country	Switzerland
Document type	Editorial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15040896
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Article ; Online: Avoiding Drug Resistance in HIV Reverse Transcriptase.

Cilento, Maria E / Kirby, Karen A / Sarafianos, Stefan G

Chemical reviews

2021 Volume 121, Issue 6, Page(s) 3271–3296

Abstract: HIV reverse transcriptase (RT) is an enzyme that plays a major role in the replication cycle of HIV and has been a key target of anti-HIV drug development efforts. Because of the high genetic diversity of the virus, mutations in RT can impart resistance ... ...

Abstract	HIV reverse transcriptase (RT) is an enzyme that plays a major role in the replication cycle of HIV and has been a key target of anti-HIV drug development efforts. Because of the high genetic diversity of the virus, mutations in RT can impart resistance to various RT inhibitors. As the prevalence of drug resistance mutations is on the rise, it is necessary to design strategies that will lead to drugs less susceptible to resistance. Here we provide an in-depth review of HIV reverse transcriptase, current RT inhibitors, novel RT inhibitors, and mechanisms of drug resistance. We also present novel strategies that can be useful to overcome RT's ability to escape therapies through drug resistance. While resistance may not be completely avoidable, designing drugs based on the strategies and principles discussed in this review could decrease the prevalence of drug resistance.
MeSH term(s)	Anti-HIV Agents/chemistry ; Anti-HIV Agents/metabolism ; Anti-HIV Agents/pharmacology ; Drug Design ; Drug Resistance, Viral ; HIV Infections/drug therapy ; HIV Reverse Transcriptase/antagonists & inhibitors ; HIV-1/drug effects ; Humans ; Models, Molecular ; Mutation ; Protein Binding ; Protein Conformation ; Reverse Transcriptase Inhibitors/chemistry ; Reverse Transcriptase Inhibitors/metabolism ; Reverse Transcriptase Inhibitors/pharmacology ; Signal Transduction ; Structure-Activity Relationship ; Virus Replication/drug effects
Chemical Substances	Anti-HIV Agents ; Reverse Transcriptase Inhibitors ; HIV Reverse Transcriptase (EC 2.7.7.49)
Language	English
Publishing date	2021-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021/acs.chemrev.0c00967
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Article ; Online: Drug Interactions in Lenacapavir-Based Long-Acting Antiviral Combinations.

Cilento, Maria E / Ong, Yee Tsuey / Tedbury, Philip R / Sarafianos, Stefan G

Viruses

2022 Volume 14, Issue 6

Abstract: Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients' quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase ... ...

Abstract	Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients' quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (integrase strand transfer inhibitor). Novel promising LA anti-HIV agents such as lenacapavir (a capsid-targeting antiviral) and islatravir (EFdA, a nucleoside reverse transcriptase translocation inhibitor) need to be explored as combination therapies. Therefore, we sought to determine whether combination of lenacapavir with islatravir, rilpivirine, or cabotegravir displayed synergy, additivity, or antagonism. We performed dose-response matrices of these drug combinations in an HIV-1 reporter cell line and subsequently analyzed the data with SynergyFinder Plus, which employs four major drug interaction models: highest single agent, Bliss independence, Loewe additivity, and zero interaction potency. Most of these models predict additive inhibition by the studied drug combinations This work highlights the importance of effective drug combinations in LA-regimens.
MeSH term(s)	Anti-HIV Agents/therapeutic use ; Drug Combinations ; Drug Interactions ; HIV Infections/drug therapy ; Humans ; Quality of Life ; Reverse Transcriptase Inhibitors/therapeutic use ; Rilpivirine/pharmacology ; Rilpivirine/therapeutic use
Chemical Substances	Anti-HIV Agents ; Drug Combinations ; Reverse Transcriptase Inhibitors ; cabotegravir, rilpivirine drug combination ; Rilpivirine (FI96A8X663)
Language	English
Publishing date	2022-05-31
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14061202
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Article ; Online: Design and Synthesis of New GS-6207 Subtypes for Targeting HIV-1 Capsid Protein.

Akther, Thamina / McFadden, William M / Zhang, Huanchun / Kirby, Karen A / Sarafianos, Stefan G / Wang, Zhengqiang

International journal of molecular sciences

2024 Volume 25, Issue 7

Abstract: HIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. ...

Abstract	HIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. We have conducted the structure-based design of two new sub-chemotypes combining the scaffold of GS-6207 and the N-terminal cap of PF74 analogs, the other important CA-targeting chemotype. The design was validated via induced-fit molecular docking. More importantly, we have worked out a general synthetic route to allow the modular synthesis of novel GS-6207 subtypes. Significantly, the desired stereochemistry of the skeleton C
MeSH term(s)	Capsid Proteins/genetics ; HIV-1/genetics ; Molecular Docking Simulation ; Anti-HIV Agents/pharmacology ; Mutation
Chemical Substances	Capsid Proteins ; Anti-HIV Agents
Language	English
Publishing date	2024-03-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25073734
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Article ; Online: Remembering Professor Walter A. Scott.

Sarafianos, Stefan G

Viruses

2014 Volume 6, Issue 10, Page(s) 3873–3874

Abstract: Walter Scott was a Biochemistry professor at the University of Miami, Miller School of Medicine and a leading figure in the field of HIV drug resistance. His untimely passing in January 2013 marked a loss for his family, as well as for students and ... ...

Abstract	Walter Scott was a Biochemistry professor at the University of Miami, Miller School of Medicine and a leading figure in the field of HIV drug resistance. His untimely passing in January 2013 marked a loss for his family, as well as for students and colleagues who knew him as a dedicated and unassuming scholar, and a lively scientist with a great sense of humor.
MeSH term(s)	Biochemistry/history ; HIV Infections/history ; HIV Infections/virology ; History, 20th Century ; History, 21st Century ; Humans ; United States
Language	English
Publishing date	2014-10-20
Publishing country	Switzerland
Document type	Biography ; Editorial ; Historical Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v6103873
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Article ; Online: 4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor.

Markowitz, Martin / Sarafianos, Stefan G

Current opinion in HIV and AIDS

2018 Volume 13, Issue 4, Page(s) 294–299

Abstract: Purpose of review: 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action, unique structure, and amongst NRTIs, unparalleled anti-HIV-1 activity. We will summarize its ... ...

Abstract	Purpose of review: 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action, unique structure, and amongst NRTIs, unparalleled anti-HIV-1 activity. We will summarize its structure and function, antiviral activity, resistance profile, and potential as an antiretroviral for use in the treatment and preexposure prophylaxis of HIV-1 infection. Recent findings: EFdA is active against wild-type (EC50 as low as 50 pmol/l) and most highly NRTI-resistant viruses. The active metabolite, EFdA-triphosphate, has been shown to have a prolonged intracellular half-life in human and rhesus (Rh) blood cells. As a result, single drug doses tested in simian immunodeficiency virus mac251-infected Rh macaques and HIV-1-infected individuals exhibited robust antiviral activity of 7-10 days duration. Preclinical studies of EFdA as preexposure prophylaxis in the Rh macaque/simian/human immunodeficiency virus low-dose intrarectal challenge model have shown complete protection when given in clinically relevant doses. Summary: EFdA is a novel antiretroviral with activity against both wild-type and NRTI-resistant viruses. As a result of the prolonged intracellular half-life of its active moiety, it is amenable to flexibility in dosing of at least daily to weekly and perhaps longer.
MeSH term(s)	Animals ; Anti-HIV Agents/chemistry ; Anti-HIV Agents/pharmacology ; Deoxyadenosines/chemistry ; Deoxyadenosines/pharmacology ; HIV Infections/drug therapy ; HIV Infections/virology ; HIV Reverse Transcriptase/antagonists & inhibitors ; HIV Reverse Transcriptase/metabolism ; HIV-1/drug effects ; HIV-1/enzymology ; HIV-1/genetics ; HIV-1/physiology ; Humans ; Reverse Transcriptase Inhibitors/chemistry ; Reverse Transcriptase Inhibitors/pharmacology
Chemical Substances	Anti-HIV Agents ; Deoxyadenosines ; Reverse Transcriptase Inhibitors ; reverse transcriptase, Human immunodeficiency virus 1 (EC 2.7.7.-) ; HIV Reverse Transcriptase (EC 2.7.7.49) ; 4'-ethynyl-2-fluoro-2'-deoxyadenosine (QPQ082R25D)
Language	English
Publishing date	2018-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0000000000000467
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Article: Drug Interactions in Lenacapavir-Based Long-Acting Antiviral Combinations

Cilento, Maria E. / Ong, Yee Tsuey / Tedbury, Philip R. / Sarafianos, Stefan G.

Viruses. 2022 May 31, v. 14, no. 6

2022

Abstract: Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients’ quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase ... ...

Abstract	Long-acting (LA) anti-HIV regimens show promise for increasing dosing intervals and consequently, improving the patients’ quality of life. The first FDA-approved LA therapy is Cabenuva, which comprises rilpivirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (integrase strand transfer inhibitor). Novel promising LA anti-HIV agents such as lenacapavir (a capsid-targeting antiviral) and islatravir (EFdA, a nucleoside reverse transcriptase translocation inhibitor) need to be explored as combination therapies. Therefore, we sought to determine whether combination of lenacapavir with islatravir, rilpivirine, or cabotegravir displayed synergy, additivity, or antagonism. We performed dose-response matrices of these drug combinations in an HIV-1 reporter cell line and subsequently analyzed the data with SynergyFinder Plus, which employs four major drug interaction models: highest single agent, Bliss independence, Loewe additivity, and zero interaction potency. Most of these models predict additive inhibition by the studied drug combinations This work highlights the importance of effective drug combinations in LA-regimens.
Keywords	RNA-directed DNA polymerase ; antagonism ; antiretroviral agents ; cell lines ; dose response ; drug interactions ; integrases ; nucleosides ; quality of life
Language	English
Dates of publication	2022-0531
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v14061202
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: HIV-2 inhibits HIV-1 gene expression via two independent mechanisms during cellular co-infection.

Yapo, Vincent / Majumder, Kinjal / Tedbury, Philip R / Wen, Xin / Ong, Yee T / Johnson, Marc C / Sarafianos, Stefan G

Journal of virology

2023 Volume 97, Issue 12, Page(s) e0187022

Abstract: Importance: Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first ... ...

Abstract	Importance: Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.
MeSH term(s)	Humans ; Coinfection/immunology ; Coinfection/virology ; HIV Long Terminal Repeat/genetics ; HIV-1/genetics ; HIV-1/immunology ; HIV-2/genetics ; HIV-2/immunology ; HIV-2/metabolism ; RNA, Viral/genetics ; tat Gene Products, Human Immunodeficiency Virus/metabolism ; Gene Expression Regulation, Viral ; Interferons/immunology ; Promoter Regions, Genetic/genetics ; Binding, Competitive ; RNA Polymerase II/metabolism ; Transcription, Genetic
Chemical Substances	RNA, Viral ; tat Gene Products, Human Immunodeficiency Virus ; Interferons (9008-11-1) ; tat peptide (17-25), Human immunodeficiency virus 1 ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2023-11-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01870-22
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Article ; Online: Exposing HIV's weaknesses.

Tedbury, Philip R / Sarafianos, Stefan G

The Journal of biological chemistry

2017 Volume 292, Issue 14, Page(s) 6027–6028

Abstract: The viral restriction factor SERINC5 inhibits HIV-1 infection via unknown mechanisms. Sood and co-workers now show that SERINC5 suppresses HIV-1 fusogenicity and increases sensitivity to neutralizing antibodies by perturbing the folding of the fusion ... ...

Abstract	The viral restriction factor SERINC5 inhibits HIV-1 infection via unknown mechanisms. Sood and co-workers now show that SERINC5 suppresses HIV-1 fusogenicity and increases sensitivity to neutralizing antibodies by perturbing the folding of the fusion machinery. This work advances our understanding of host-virus interactions and provides a compelling case for considering the host immune system in studies of restriction factor mechanisms.
MeSH term(s)	Antibodies, Neutralizing/immunology ; HIV Antibodies/immunology ; HIV Infections/immunology ; HIV-1/immunology ; Humans ; Membrane Proteins/immunology ; Protein Folding ; Virus Internalization
Chemical Substances	Antibodies, Neutralizing ; HIV Antibodies ; Membrane Proteins ; SERINC5 protein, human
Language	English
Publishing date	2017-04-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.H117.777714
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