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CATEGORIES:Thesis/Dissertations
DESCRIPTION:Advisors: Shuowei Cai, Professor, Department of Chemistry and B
 iochemistry, Dissertation Advisor. Xiaofei Jia, Associate Professor, Depar
 tment of Biomedical Sciences, Florida State University College of Medicine
 , Tallahassee, FL, Dissertation Advisor. Committee members: Catherine Neto
 , Professor, Department of Chemistry and Biochemistry, Dissertation Commit
 tee. Tracie Ferreira, Professor, Department of Bioengineering, Dissertatio
 n Committee. Abstract: Human immunodeficiency virus type 1 (HIV-1) remains
  a major global health challenge. Although current treatments effectively 
 suppress viral replication, they are unable to eliminate infected cells. T
 he viral accessory protein Nef contributes substantially to HIV-1 persiste
 nce: it downregulates multiple host immune receptors and restriction facto
 rs and thus enables infected cells to evade immune surveillance. Consequen
 tly, Nef represents an attractive therapeutic target; its inhibition shoul
 d restore host immune functions and promote the clearance of HIV-1 infecte
 d cells, which may lead to a functional cure. The development of Nef inhib
 itor has two major limitations: lack of enzymatic activity and thus a drug
 gable-site and the great conformational dynamic of the Nef protein. Succes
 sful development of Nef inhibitors would require competent screening assay
 (s) that can address these issues. Chapter 2 of this dissertation describe
 s our work in developing such an assay for the discovery of inhibitors of 
 Nef-mediated MHC-I downregulation. Here, time-resolved fluorescence resona
 nce energy transfer (TR-FRET) was used, and the assay signal is associated
  with complex assembly between MHC-I cytoplasmic domain (MHC-ICD), Nef, an
 d clathrin AP1. The optimized assay is robust, and its suitability for hig
 h-throughput screening (HTS) was validated through a proof-of-concept scre
 ening of a medium-sized library. Chapter 3 of this dissertation describes 
 our work in developing cyclic MHC-ICD-mimetic peptides as potential inhibi
 tors of Nef-mediated MHC-I downregulation. Robust assays were developed to
  investigate the interactions between cyclic peptides and the Nef/AP1 comp
 lex and thus help evaluate peptide inhibitors developed by our collaborato
 rs. The framework established here for evaluating cyclopeptide hits also p
 aved the way for future structural studies aimed at elucidating the inhibi
 tor-Nef/AP1 interaction to guide the rational optimization of future inhib
 itors. Chapter 4 of this dissertation describes our work in using cryo-EM 
 to study the structural basis of HIV-1 Nef-mediated SERINC5 downregulation
 . A novel AP2 hemicomplex was designed to stabilize the conformation of Ne
 f and thus facilitate single-particle cryo-EM analysis. In addition, to ad
 dress the weak interaction between Nef/AP2 and the intracellular loop 4 (I
 CL4) of SERINC5, a chemical crosslinking strategy was employed to capture 
 the assembly complex. Prepared samples allowed cryo-EM analysis leading to
  a 2.88 脜 electron density map. Structural solution was achieved for the 
 AP2 components as well as the folded core domain of Nef. Density for SERIN
 C5 ICL4 has also been observed; however, the poor quality of the density h
 as prevented successful building of the ICL4 structure. This milestone suc
 cess has nonetheless provided important guidance for further construct opt
 imization and subsequent structural studies of Nef-mediated SERINC5 downre
 gulation. Zoom Meeting ID: 970 8991 3327 https://fsu.zoom.us/j/97089913327
 #success听\nEvent page: /events/cms/7-31-26-defense-
 by-kequan-wang-inhibitors-screening-against-hiv-1-nef.php\nEvent link: htt
 ps://fsu.zoom.us/j/97089913327#success
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</script><p><strong>Advisors:</strong></p>\
 n<p>Shuowei Cai\, Professor\, Department of Chemistry and Biochemistry\, D
 issertation Advisor.</p>\n<p>Xiaofei Jia\, Associate Professor\, Departmen
 t of Biomedical Sciences\, Florida State University College of Medicine\, 
 Tallahassee\, FL\, Dissertation Advisor.</p>\n<p><strong>Committee members
 :</strong></p>\n<p>Catherine Neto\, Professor\, Department of Chemistry an
 d Biochemistry\, Dissertation Committee.</p>\n<p>Tracie Ferreira\, Profess
 or\, Department of Bioengineering\, Dissertation Committee.</p>\n<p><stron
 g>Abstract:</strong></p>\n<p>Human immunodeficiency virus type 1 (HIV-1) r
 emains a major global health challenge. Although current treatments effect
 ively suppress viral replication\, they are unable to eliminate infected c
 ells. The viral accessory protein Nef contributes substantially to HIV-1 p
 ersistence: it downregulates multiple host immune receptors and restrictio
 n factors and thus enables infected cells to evade immune surveillance. Co
 nsequently\, Nef represents an attractive therapeutic target\; its inhibit
 ion should restore host immune functions and promote the clearance of HIV-
 1 infected cells\, which may lead to a functional cure.</p>\n<p>The develo
 pment of Nef inhibitor has two major limitations: lack of enzymatic activi
 ty and thus a druggable-site and the great conformational dynamic of the N
 ef protein. Successful development of Nef inhibitors would require compete
 nt screening assay(s) that can address these issues. Chapter 2 of this dis
 sertation describes our work in developing such an assay for the discovery
  of inhibitors of Nef-mediated MHC-I downregulation. Here\, time-resolved 
 fluorescence resonance energy transfer (TR-FRET) was used\, and the assay 
 signal is associated with complex assembly between MHC-I cytoplasmic domai
 n (MHC-ICD)\, Nef\, and clathrin AP1. The optimized assay is robust\, and 
 its suitability for high-throughput screening (HTS) was validated through 
 a proof-of-concept screening of a medium-sized library.</p>\n<p>Chapter 3 
 of this dissertation describes our work in developing cyclic MHC-ICD-mimet
 ic peptides as potential inhibitors of Nef-mediated MHC-I downregulation. 
 Robust assays were developed to investigate the interactions between cycli
 c peptides and the Nef/AP1 complex and thus help evaluate peptide inhibito
 rs developed by our collaborators. The framework established here for eval
 uating cyclopeptide hits also paved the way for future structural studies 
 aimed at elucidating the inhibitor-Nef/AP1 interaction to guide the ration
 al optimization of future inhibitors.</p>\n<p>Chapter 4 of this dissertati
 on describes our work in using cryo-EM to study the structural basis of HI
 V-1 Nef-mediated SERINC5 downregulation. A novel AP2 hemicomplex was desig
 ned to stabilize the conformation of Nef and thus facilitate single-partic
 le cryo-EM analysis. In addition\, to address the weak interaction between
  Nef/AP2 and the intracellular loop 4 (ICL4) of SERINC5\, a chemical cross
 linking strategy was employed to capture the assembly complex. Prepared sa
 mples allowed cryo-EM analysis leading to a 2.88 脜 electron density map. 
 Structural solution was achieved for the AP2 components as well as the fol
 ded core domain of Nef. Density for SERINC5 ICL4 has also been observed\; 
 however\, the poor quality of the density has prevented successful buildin
 g of the ICL4 structure. This milestone success has nonetheless provided i
 mportant guidance for further construct optimization and subsequent struct
 ural studies of Nef-mediated SERINC5 downregulation.</p>\n<p>Zoom Meeting 
 ID: 970 8991 3327</p>\n<p>听</p><p>Event page: <a h
 ref="/events/cms/7-31-26-defense-by-kequan-wang-inhi
 bitors-screening-against-hiv-1-nef.php">/events/cms/
 7-31-26-defense-by-kequan-wang-inhibitors-screening-against-hiv-1-nef.php<
 /a><br>Event link: </p></body></html>
DTSTAMP:20260725T145105
DTSTART;TZID=America/New_York:20260731T100000
DTEND;TZID=America/New_York:20260731T120000
LOCATION:Virtual
SUMMARY;LANGUAGE=en-us:PhD Dissertation Defense by Kequan Wang, "Inhibitors
  Screening against HIV-1 Nef-Mediated MHC-I Downregulation and Structural 
 Studies of Nef-Mediated SERINC5 Downregulation" 
UID:cce4f7864581b314a17df6713ce06b2a@www.umassd.edu
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