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Biological and Pharmacological Characterization of Novel HBV Ribonuclease H Inhibitors /

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Biological and Pharmacological Characterization of Novel HBV Ribonuclease H Inhibitors // Molly E Woodson.
作者:	Woodson, Molly E.,
面頁冊數:	1 electronic resource (199 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-07, Section: B.
提要註:	Chronic hepatitis B remains a major global health burden with an unmet medical need, resulting in greater than one million annual deaths due to hepatitis B virus (HBV) associated liver complications, such as liver cancer and failure. Current treatment with nucleos(t)ide analogs suppresses viremia in most patients, but treatment cessation often results in viremia reoccurrence. As such, the development of novel anti-HBV therapies with new targets is required. We have identified the HBV ribonuclease H (RNase H) domain as an attractive drug target and previous work has determined RNase H inhibitors have sub-micromolar efficacy against HBV replication, but they lack the pharmacological evaluation that is required in preclinical studies for the identification of lead candidates. Previous work allowed us to eliminate compounds from the HID subgroup from lead candidate identification and here I evaluated the biological and pharmacological properties of compounds from the HPD, α-HT, and HNO chemotypes. I concluded due to a lack of improved efficacy and poor passive permeabilities of the HNOs, they should be excluded from the lead candidate identification. Additionally, after carrying 36 α-HTs through an in-depth, in vitro, drug discovery testing funnel, I concluded that they should be excluded from our drug discovery campaign because they are likely to cause drug-drug interactions and off-target effects at concentrations required to inhibit HBV replication. Finally, after assessing the anti-HBV efficacy and cytotoxicity of greater than 150 oxime HPDs, I evaluated 29 of them in an early- and late-stage drug discovery testing funnel. Notably, I identified two oxime HPDs, 1618 and 1620, that are safe, effective, and exhibit pharmacological properties similar to drugs on the market. As such, they warrant further in vivo evaluation as novel HBV RNase H inhibitors. Importantly, my in-depth evaluation of HBV RNase H inhibitors provided critical knowledge as we continue our efforts to identify compounds that could contribute to a functional cure for chronic hepatitis B.
Contained By:	Dissertations Abstracts International86-07B.
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31766321
ISBN:	9798302150257

Biological and Pharmacological Characterization of Novel HBV Ribonuclease H Inhibitors /
Woodson, Molly E.,

Biological and Pharmacological Characterization of Novel HBV Ribonuclease H Inhibitors /Molly E Woodson. - 1 electronic resource (199 pages)

Source: Dissertations Abstracts International, Volume: 86-07, Section: B.

Chronic hepatitis B remains a major global health burden with an unmet medical need, resulting in greater than one million annual deaths due to hepatitis B virus (HBV) associated liver complications, such as liver cancer and failure. Current treatment with nucleos(t)ide analogs suppresses viremia in most patients, but treatment cessation often results in viremia reoccurrence. As such, the development of novel anti-HBV therapies with new targets is required. We have identified the HBV ribonuclease H (RNase H) domain as an attractive drug target and previous work has determined RNase H inhibitors have sub-micromolar efficacy against HBV replication, but they lack the pharmacological evaluation that is required in preclinical studies for the identification of lead candidates. Previous work allowed us to eliminate compounds from the HID subgroup from lead candidate identification and here I evaluated the biological and pharmacological properties of compounds from the HPD, α-HT, and HNO chemotypes. I concluded due to a lack of improved efficacy and poor passive permeabilities of the HNOs, they should be excluded from the lead candidate identification. Additionally, after carrying 36 α-HTs through an in-depth, in vitro, drug discovery testing funnel, I concluded that they should be excluded from our drug discovery campaign because they are likely to cause drug-drug interactions and off-target effects at concentrations required to inhibit HBV replication. Finally, after assessing the anti-HBV efficacy and cytotoxicity of greater than 150 oxime HPDs, I evaluated 29 of them in an early- and late-stage drug discovery testing funnel. Notably, I identified two oxime HPDs, 1618 and 1620, that are safe, effective, and exhibit pharmacological properties similar to drugs on the market. As such, they warrant further in vivo evaluation as novel HBV RNase H inhibitors. Importantly, my in-depth evaluation of HBV RNase H inhibitors provided critical knowledge as we continue our efforts to identify compounds that could contribute to a functional cure for chronic hepatitis B.

English

ISBN: 9798302150257Subjects--Topical Terms:

186550
Biochemistry.
Subjects--Index Terms:

Drug discovery

Biological and Pharmacological Characterization of Novel HBV Ribonuclease H Inhibitors /
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