HIV Capsid Inhibitors Beyond PF74
1
Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri, Kansas City, MO 64108, USA
2
Kansas City School of Medicine, University of Missouri, Kansas City, MO 64108, USA
3
Department of Pathology, Truman Medical Center, Kansas City, MO, 64108, USA
4
Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
5
Department of Chemistry, University of Missouri, Columbia, MO 65211, USA
6
Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
7
Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65211, USA
8
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, 14186 Stockholm, Sweden
*
Authors to whom correspondence should be addressed.
Diseases 2019, 7(4), 56; https://doi.org/10.3390/diseases7040056
Received: 20 September 2019 / Revised: 21 October 2019 / Accepted: 27 October 2019 / Published: 30 October 2019
(This article belongs to the Section Infectious Disease)
Human immunodeficiency virus (HIV) capsid plays important roles at multiple stages of viral replication. At the initial stages, controlled uncoating (disassembly) of the capsid ensures efficient reverse transcription of the single-stranded RNA genome, into the double-stranded DNA. Whereas at later stages, a proper assembly of capsid ensures the formation of a mature infectious virus particle. Hence, the inhibition of capsid assembly and/or disassembly has been recognized as a potential therapeutic strategy, and several capsid inhibitors have been reported. Of these, PF-3450074 (PF74) has been extensively studied. Recently reported GS-CA inhibitors (GS-CA1 and GS-6207), have shown a strong potential and appear to contain a PF74 scaffold. The location of resistance mutations and the results of structural studies further suggest that GS-CA compounds and PF74 share the same binding pocket, which is located between capsid monomers. Additionally, phenylalanine derivatives containing the PF74 scaffold show slightly enhanced capsid inhibiting activity. A comparison of capsid structures in complex with host factors and PF74, reveals the presence of common chemical entities at topologically equivalent positions. Here we present the status of capsid inhibitors that contain PF74 scaffolds and propose that the PF74 scaffold may be used to develop strong and safe capsid inhibitors.
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Keywords:
human immunodeficiency virus; capsid; assembly; small molecule inhibitors; PF74; GS-CA1; GS-6207; disassembly; uncoating
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MDPI and ACS Style
McArthur, C.; Gallazzi, F.; Quinn, T.P.; Singh, K. HIV Capsid Inhibitors Beyond PF74. Diseases 2019, 7, 56.
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