Jiashu Xie, PhD

Research Summary

Current research in the Pharmacokinetics (PK) lab has focused on profiling the in vitro ADME (absorption, distribution, metabolism, and excretion) and in vivo PK properties of lead compounds from medicinal chemistry efforts. Our work can provide a basis for chemists to select and optimize the leads that have desirable “drug-like” properties, necessary for drug candidate selection before the preclinical and clinical development. A wide range of ADME/PK assays and techniques are employed in our research. These include:

• Microsomal stability, S9 stability, Plasma stability, Aqueous stability
• Cytochrome P450 inhibition, reaction phenotyping
• Plasma protein binding, brain tissue binding, blood to plasma ratio
• Solubility
• Caco-2, MDCK and PAMPA permeability
• Oral bioavailability and tissue distribution in rodent
• PK modeling and simulation using Phoenix WinNonlin®
• LC/MS/MS bioanalysis

Our other research focus is to improve drug response in combination chemotherapy and combat cancer drug resistance. Particularly, we devote a large portion of our research to identifying novel compounds that impact cellular uptake or inhibit drug efflux - the most common mechanism underlying acquired drug resistance in cancer, pinpointing the transporters or targets involved in these processes, and evaluating regimens to produce desirable anti-cancer responses.

• Belhadj Z, Offei S, Jacobson B. A., Cambron D, Kratzke R. A., Wang Z, Xie J *. Cancer sensitizing effect of deazaflavin analogs is associated with increased intracellular drug accumulation. Eur J Pharm Sci. 2024; 193: 106686. https://doi.org/10.1016/j.ejps.2023.106686
• Xie W, Jiang R, Xie J, Vince R, More SS. Geometric Isomer of Guanabenz Confers Hepatoprotection to a Murine Model of Acetaminophen Toxicity. Chem Res Toxicol. 2023; 36(7): 1071-1080. 
• He T, Edwards TC, Majima R, Jung E, Kankanala J, Xie J, Geraghty RJ, Wang Z. Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization. Bioorg Chem. 2022; 129: 106198.
• Xie W, Cao B, Zhu H, Raza A, Juckel N, Xie J, Jiang R, Vince R, Lee MK, More SS. Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer's Disease. J Med Chem. 2022; 65(21): 14441-14455.
• Rao SP, Xie W, Christopher Kwon YI, Juckel N, Xie J, Dronamraju VR, Vince R, Lee MK, More SS. Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo. Redox Biol. 2022; 57: 102484.
• Jung E, Soto-Acosta R, Xie J, Wilson DJ, Dreis CD, Majima R, Edwards TC, Geraghty RJ, Chen L. Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase. ACS Med Chem Lett. 2022; 13(9): 1477-1484.
• He T, Edwards TC, Xie J, Aihara H, Geraghty RJ, Wang Z. 4,5-Dihydroxypyrimidine methyl carboxylates, carboxylic acids, and carboxamides as inhibitors of human cytomegalovirus pUL89 endonuclease. J Med Chem. 2022; 65(7): 5830-5849.
• Senaweera S, Edwards TC, Kankanala J, Wang Y, Sahani RL, Xie J, Geraghty RJ, Wang Z. Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV). Acta Pharm Sin B. 2022; 12(4): 1671-1684.
• Soto-Acosta R, Edwards TC, Dreis CD, Krishna VD, Cheeran MC-J, Qiu L, Xie J, Bonnac LF, Geraghty RJ. Enhancing the Antiviral Potency of Nucleobases for Potential Broad-Spectrum Antiviral Therapies. Viruses. 2021; 13(12): 2508.
• Christopher Kwon YI, Xie W, Zhu H, Xie J, Shinn K, Juckel N, Vince R, More SS, Lee MK. (γ)-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer's Disease-like Pathology and Neurodegeneration in a Mouse Model. Antioxidants (Basel). 2021; 10(11): 1796. 
• Xie J *, Jiang R, Xie W, Cao B, More SS. LC-MS/MS determination of guanabenz E/Z isomers and its application to in vitro and in vivo DMPK profiling studies. J Pharm Biomed Anal. 2021; 205: 114331. https://doi.org/10.1016/j.jpba.2021.114331
• Wang L, Edwards TC, Sahani RL, Xie J, Aihara H, Geraghty RJ, Wang Z. Metal binding 6-arylthio-3-hydroxypyrimidine-2,4-diones inhibited human cytomegalovirus by targeting the pUL89 endonuclease of the terminase complex. Eur J Med Chem. 2021; 222: 113640.
• Senaweera S, Du H, Zhang H, Kirby KA, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Discovery of new small molecule hits as hepatitis B virus capsid assembly modulators: structure and pharmacophore-based approaches. Viruses. 2021; 13(5): 770.
• Xie J *, Wang Z. Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment. Acta Pharm Sin B. 2021; 11(6): 1607-1616. https://doi.org/10.1016/j.apsb.2021.03.028
• Wang L, Casey MC, Vernekar SKV, Sahani RL, Kirby KA, Du H, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Novel PF74-like small molecules targeting the HIV-1 capsid protein: balance of potency and metabolic stability. Acta Pharm Sin B. 2021;11(3): 810-822.
• Sahani RL, Diana-Rivero R, Vernekar SKV, Wang L, Du H, Zhang H, Castaner AE, Casey MC, Kirby KA, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Design, synthesis and characterization of HIV-1 CA-targeting small molecules: conformational constraint of PF74. Viruses. 2021; 13(3): 479.
• Sahani, RL, Akther T, Cilento, ME, Castaner AE, Zhang H, Kirby KA, Xie J, Sarafianos SG, Wang Z. Potency and metabolic stability: a molecular hybrid case in the design of novel PF74-like small molecules targeting HIV-1 capsid protein. RSC Med. Chem. 2021; 12: 2031.
• Wang L, Casey MC, Vernekar SKV, Sahani RL, Kankanala J, Kirby KA, Du H, Hachiya A, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Novel HIV-1 capsid-targeting small molecules of the PF74 binding site. Eur J Med Chem. 2020; 204: 112626.
• Wang L, Casey MC, Vernekar SKV, Do HT, Sahani RL, Kirby KA, Du H, Hachiya A, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Chemical profiling of HIV-1 capsid-targeting antiviral PF74. Eur J Med Chem. 2020; 200: 112427.
• Vernekar SKV, Sahani RL, Casey MC, Kankanala J, Wang L, Kirby KA, Du H, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules. Viruses. 2020; 12(4): 452.
• Kiselev E, Ravji A, Kankanala J, Xie J, Wang Z, Pommier Y. Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. DNA Repair (Amst). 2020; 85: 102747.
• Xie W, Xie J, Vince R, More SS. Guanabenz Attenuates Acetaminophen-Induced Liver Toxicity and Synergizes Analgesia in Mice. Chem Res Toxicol. 2020; 33(1): 162-171.
• Kankanala J, Ribeiro CJA, Kiselev E, Ravji A, Williams J, Xie J, Aihara H, Pommier Y, Wang Z. Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide. J Med Chem. 2019; 62(9): 4669-4682.
• Ding R, Zhang T, Wilson DJ, Xie J, Williams J, Xu Y, Ye Y, Chen L. Discovery of Irreversible p97 Inhibitors. J Med Chem. 2019; 62(5): 2814-2829.
• Tang J, Huber AD, Pineda DL, Boschert KN, Wolf JJ, Kankanala J, Xie J, Sarafianos SG, Wang Z. 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors. Eur J Med Chem. 2019; 164: 179-192.
• Ribeiro CJA, Kankanala J, Xie J, Williams J, Aihara H, Wang Z. Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors. Bioorg Med Chem Lett. 2019; 29(2): 257-261.
• Wang L, Tang J, Huber AD, Casey MC, Kirby KA, Wilson DJ, Kankanala J, Xie J, Parniak MA, Sarafianos SG, Wang Z. 6-Arylthio-3-hydroxypyrimidine-2,4-diones potently inhibited HIV reverse transcriptase-associated RNase H with antiviral activity. Eur J Med Chem. 2018; 156: 652-665.
• Sadhu SS, Wang S, Dachineni R, Averineni RK, Seefeldt T, Xie J, Tummala H, Bhat GJ, Guan X. In Vitro and In Vivo Antimetastatic Effect of Glutathione Disulfide Liposomes. Cancer Growth Metastasis. 2017; 10: 1-11.
• Zhou W, Wang Y, Xie J, Geraghty RJ. A fluorescence-based high-throughput assay to identify inhibitors of tyrosylprotein sulfotransferase activity. Biochem Biophys Res Commun. 2017; 482(4): 1207-1212.
• Ai T, Willett R, Williams J, Ding R, Wilson DJ, Xie J, Kim DH, Puertollano R, Chen L. N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy. ACS Med Chem Lett. 2017; 8(1): 90-95.
• Daly MB, Roth ME, Bonnac L, Maldonado JO, Xie J, Clouser CL, Patterson SE, Kim B, Mansky LM. Dual anti-HIV mechanism of clofarabine. Retrovirology. 2016; 13(1): 1-12.
• Ding R, Zhang T, Xie J, Williams J, Ye Y, Chen L. Eeyarestatin I derivatives with improved aqueous solubility. Bioorg Med Chem Lett. 2016; 26(21): 5177-5181.
• Sadhu SS, Xie J, Zhang H, Perumal O, Guan X. Glutathione Disulfide Liposomes - a Research Tool for the Study of Glutathione Disulfide Associated Functions and Dysfunctions. Biochem Biophys Rep. 2016; 7: 225-229.
• Wu B, Tang J, Wilson DJ, Huber AD, Casey MC, Ji J, Kankanala J, Xie J, Sarafianos SG, Wang Z. 3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase H. J Med Chem. 2016; 59(13): 6136-6148.
• Rawson JM, Roth ME, Xie J, Daly MB, Clouser CL, Landman SR, Reilly CS, Bonnac L, Kim B, Patterson SE, Mansky LM. Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase. Bioorg Med Chem. 2016; 24(11): 2410-2422.
• Ai T, Wilson DJ, More SS, Xie J, Chen L. 5-((3-Amidobenzyl)oxy)nicotinamides as Sirtuin 2 Inhibitors. J Med Chem. 2016; 59(7): 2928-2941.
• Rawson JM, Daly MB, Xie J, Clouser CL, Landman SR, Reilly CS, Bonnac L, Kim B, Patterson SE, Mansky LM. 5-Azacytidine Enhances the Mutagenesis of HIV-1 by Reduction to 5-Aza-2'-Deoxycytidine. Antimicrob Agents Chemother. 2016; 60(4): 2318-2325.
• Ai T, Qiu L, Xie J, Geraghty RJ, Chen L. Design and synthesis of an activity-based protein profiling probe derived from cinnamic hydroxamic acid. Bioorg Med Chem. 2016; 24(4): 686-692.
• Muthyala R, Shin WS, Xie J, Sham YY. Discovery of 1-hydroxypyridine-2-thiones as selective histone deacetylase inhibitors and their potential application for treating leukemia. Bioorg Med Chem Lett. 2015; 25(19): 4320-4324.
• Xie J, Potter A, Xie W, Lynch C, Seefeldt T. Evaluation of a dithiocarbamate derivative as a model of thiol oxidative stress in H9c2 rat cardiomyocytes. Free Radic Biol Med. 2014; 70: 214-222.
• Xie J, Ge Q. Matrix effects in bioanalysis by LC/MS. Chin J Pharm Anal. 2008; 28(8): 1386-1389.
• Xie J, Ding C, Ge Q, Zhou Z, Zhi X. Simultaneous determination of ginkgolides A, B, C and bilobalide in plasma by LC-MS/MS and its application to the pharmacokinetic study of Ginkgo biloba extract in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2008; 864(1-2): 87-94.

Research Funding Grants

8/1/2022 - 7/31/2027
Discovery of SARS-CoV-2 antivirals using a replicon assay
R01 AI167356 NIH/NIAID
Role: Co-Investigator (PIs: Stefan Sarafianos and Zhengqiang Wang)

6/15/2022 - 5/31/2024
Bi-substrate Inhibitors of SARS-CoV-2 Nsp14 Methyltransferase
R21 AI166065 NIH/NIAID
Role: Co-Investigator (PI: Liqiang Chen)

6/24/2021 - 5/31/2026
Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles
R01 AI120860 NIH/NIAID
Role: Co-Investigator (PIs: Stefan Sarafianos and Zhengqiang Wang)

2/1/2020 - 1/31/2022
Optimizing Zika NS5 Methyltransferase Inhibitors
R21 AI151427 NIH/NIAID
Role: Co-Investigator (PI: Liqiang Chen)

1/25/2019 - 12/31/2024
Discovery and development of novel anti-HCMV agents targeting the UL89 terminase protein
R01 AI136982 NIH/NIAID
Role: Co-Investigator (PIs: Robert Geraghty and Zhengqiang Wang)

6/14/2016 - 5/31/2021
Taking aim at HBV eradication using novel NRTIs and capsid effectors
R01 AI121315 NIH/NIAID
Role: Co-Investigator (PIs: Stefan Sarafianos and Zhengqiang Wang)