Synthesis of P1 and Cap-P2 Fragments of Novel SARS-CoV-2 Protease Inhibitors Öffentlichkeit

Abstract

The Covid-19 pandemic has led to devastating global public health consequences. As a viral, contagious disease, it has caused millions of deaths worldwide and continues to pose a threat to immunocompromised individuals. SARS-CoV-2’s use of a main protease to cleave viral polypeptides provides an excellent target for Covid-19 therapeutics due to its low toxicity. Several SARS-CoV-2 peptidomimetic protease inhibitors have been developed to prevent the cleavage of nascent proteins, culminating in approval for Paxlovid (nirmatrelvir) and Xiannuoxin (simnotrelvir). These compounds may not provide ample treatment for potential variants of Covid-19 and likewise exclude many immunocompromised patient groups from their benefits due to lack of potency and a short half-life. The Laboratory of Biochemical Pharmacology is developing and optimizing more potent SARS-CoV-2 inhibitors that offer a more dynamic, enduring solution for Covid-19 patients. We present progress in completing a synthesis of the Cap-P2 fragment and optimizing a synthesis of the P1 fragment, which will eventually be combined and integrated into several SARS-CoV-2 protease inhibitors that are expected to be more potent.

Table of Contents

Table of Contents 

Chapter 1: Introduction…………………………………………………………………………1       

1.1. SARS-CoV-2………………………………………………………………………..………1  

1.2. SARS-CoV-2 protease inhibitors…………………………………………………......5

1.3. Toward the next generation of SARS-CoV-2 protease inhibitors…...………..12

1.4. Target compounds……………………………………………………………………....12                                                                                  

Chapter 2: Synthesis…………………………………………………………………………….13

2.1. Synthesis of the P1 subunit…………………………………………………………...13

2.2. Synthesis of the Cap-P2 subunit…………………………………………………..…18

Chapter 3: Conclusions and future directions……………………………………….……19

Chapter 4: Supporting information………………………………………………………… 19

4.1. General information……………………………………………………………….…...19

4.2. Synthetic procedures……………………………………………………………….…..20

Abbreviations………………………………………………………………..……………………30

References……………………………………………………………………...………………….31

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Biochemistry Chemistry, Organic
Stichwort	Medicinal Chemistry Covid-19 SARS-CoV-2 Protease Inhibitor Synthetic Chemistry Organic Chemistry
Committee Chair / Thesis Advisor	Dr. Franck Amblard, Emory University
Committee Members	Dr. Richard Himes, Emory University Dr. Matthew Weinschenk, Emory University

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