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• W2464102004 endingPage "8197" @default.
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• W2464102004 abstract "ABSTRACT HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert -butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated. IMPORTANCE Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action." @default.
• W2464102004 created "2016-07-22" @default.
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• W2464102004 date "2016-09-15" @default.
• W2464102004 modified "2023-09-25" @default.
• W2464102004 title "Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396" @default.
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• W2464102004 cites W1585440676 @default.
• W2464102004 cites W1594514074 @default.
• W2464102004 cites W1595806441 @default.
• W2464102004 cites W1611298747 @default.
• W2464102004 cites W1659719610 @default.
• W2464102004 cites W1753916721 @default.
• W2464102004 cites W1823429634 @default.
• W2464102004 cites W1924577704 @default.
• W2464102004 cites W1932084946 @default.
• W2464102004 cites W1964146897 @default.
• W2464102004 cites W1973282984 @default.
• W2464102004 cites W1994410560 @default.
• W2464102004 cites W1999148331 @default.
• W2464102004 cites W2002445611 @default.
• W2464102004 cites W2006771360 @default.
• W2464102004 cites W2013652077 @default.
• W2464102004 cites W2018697541 @default.
• W2464102004 cites W2024131050 @default.
• W2464102004 cites W2028985917 @default.
• W2464102004 cites W2048107562 @default.
• W2464102004 cites W2048475719 @default.
• W2464102004 cites W2052389336 @default.
• W2464102004 cites W2062967707 @default.
• W2464102004 cites W2077795431 @default.
• W2464102004 cites W2087978946 @default.
• W2464102004 cites W2102953571 @default.
• W2464102004 cites W2113606450 @default.
• W2464102004 cites W2115382947 @default.
• W2464102004 cites W2115851369 @default.
• W2464102004 cites W2116262094 @default.
• W2464102004 cites W2117867057 @default.
• W2464102004 cites W2122102984 @default.
• W2464102004 cites W2123369658 @default.
• W2464102004 cites W2123634339 @default.
• W2464102004 cites W2128580131 @default.
• W2464102004 cites W2128780965 @default.
• W2464102004 cites W2128936065 @default.
• W2464102004 cites W2132762790 @default.
• W2464102004 cites W2134403038 @default.
• W2464102004 cites W2134977815 @default.
• W2464102004 cites W2136683144 @default.
• W2464102004 cites W2141935651 @default.
• W2464102004 cites W2142892346 @default.
• W2464102004 cites W2145652748 @default.
• W2464102004 cites W2146597139 @default.
• W2464102004 cites W2146667353 @default.
• W2464102004 cites W2151116772 @default.
• W2464102004 cites W2152539875 @default.
• W2464102004 cites W2153005663 @default.
• W2464102004 cites W2155183647 @default.
• W2464102004 cites W2155380502 @default.
• W2464102004 cites W2155921043 @default.
• W2464102004 cites W2156696460 @default.
• W2464102004 cites W2156981438 @default.
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• W2464102004 doi "https://doi.org/10.1128/jvi.01075-16" @default.
• W2464102004 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5008107" @default.
• W2464102004 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27384665" @default.
• W2464102004 hasPublicationYear "2016" @default.
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