자료유형  

 학위논문

Control Number  

0017163500

International Standard Book Number  

9798384449171

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Bajaj, Teena.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of California, Berkeley., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

67 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-04, Section: B.

General Note  

Advisor: Murthy, Niren.

Dissertation Note  

Thesis (Ph.D.)--University of California, Berkeley, 2024.

Summary, Etc.  

요약The emergence and rapid spread of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 (SCoV-2) caused catastrophic levels of morbidity in the world and presented the unmet need for treatments and drugs urgently. Small molecule therapeutics have tremendous potential to develop into antivirals and prevent the spread of infection. SCoV-2 genome encodes for 16 non-structural proteins (Nsps) that have been proven as potential target candidates. Two vital proteins, Papain-like protease (PLpro) (Papain-like protease, from Nsp3) and Non-structural protein 15 (Nsp15) were chosen as therapeutic targets to combat the SCoV-2 virus. PLpro is an essential protein that cleaves the polyprotein into its individual proteins to form a replication-transcription complex for viral replication and synthesis. On another hand, Nsp15 is a crucial protein that evades the host immune response by cleaving the viral RNA, therefore, Nsp15 inhibition stimulates the protective response. Both nsps are highly conserved proteins and the development of drugs against them could also act as an initial step for future coronavirus pandemics. To find the covalent inhibitors of PLpro and Nsp15, the electrophile library was screened against these two proteins using their respective fluorescent-based, high-throughput screening assay. To find the inhibitors against the PLpro, a chemical library was screened against the recombinantly purified PLpro using a fluorescent-based high throughput screening assay. One compound, based on mercaptopyrimidine inhibited PLpro invitro and SARS-CoV-2 viral replication in Vero E6 cells. This compound presented the first example of a thiol-targeted reversible covalent inhibitor of PLpro. In the case of Nsp15, an acrylamide-based electrophile library was screened to find cysteine-binding inhibitors. This discovered a new class of Nsp15 covalent inhibitors. This study not only discovered new covalent lead hits against crucial proteins from SCoV-2, but also a new platform to develop new potent drugs against coronaviruses for future pandemics.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Epidemiology.

Index Term-Uncontrolled  

Papain-like protease

Index Term-Uncontrolled  

Mercaptopyrimidine

Index Term-Uncontrolled  

Covalent inhibitors

Added Entry-Corporate Name  

University of California, Berkeley Comparative Biochemistry

Host Item Entry  

Dissertations Abstracts International. 86-04B.

Electronic Location and Access  

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Control Number  

joongbu:658542