Design, Synthesis and Biological Evaluation of Small Molecules that Inhibit HIV-1 Entry and Sensitize HIV-1 Infected Cells to Immune Responses / Melissa C. Grenier.

Format:

Book

Thesis/Dissertation

Author/Creator:

Grenier, Melissa C., author.

Contributor:

Smith, Amos B., degree supervisor.

University of Pennsylvania. Department of Chemistry, degree granting institution.

Language:

English

Subjects (All):

Organic chemistry.

Chemistry--Penn dissertations.

Penn dissertations--Chemistry.

Local Subjects:

Organic chemistry.

Chemistry--Penn dissertations.

Penn dissertations--Chemistry.

Genre:

Academic theses.

Physical Description:

1 online resource (490 pages)

Contained In:

Dissertations Abstracts International 81-03B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

With over 37 million people living with HIV worldwide and an estimated 2 million new infections reported last year, the need to derive novel strategies aimed not only at protection from, but more importantly at eradication of HIV-1 infection remains a critical worldwide challenge. Our program project aims to develop potent, broadly active small molecule CD4 mimetic compounds (CD4mc) that promote multiple biological responses. While these small molecules were initially optimized for inhibition of HIV-1 entry, recent studies have demonstrated that these small molecule CD4mc synergize with antibodies to control and potentially eradicate HIV-1 infection both by sensitization of viral particles to neutralization and sensitization of HIV-1 infected cells to antibody-dependent cellular cytotoxicity (ADCC). The first part of my thesis describes the development of a late-stage derivatization strategy for the synthesis of 1,2,5,7-tetrasubstituted aminoindane small molecule CD4mc and the corresponding biological evaluation. The second part highlights the discovery and development of a new structural class of small molecule CD4mc with the capacity to elicit ADCC responses that was identified through a high-throughput screen performed by our collaborator. This project focused on efforts both to synthesize a broad set of analogues based on the original HTS hit, utilizing parallel synthetic library design, and to define the structure-activity relationships (SAR) observed. Recent crystallographic studies identified the binding site of this new class of CD4mc, which has led to the design of new, more potent analogues.

Notes:

Source: Dissertations Abstracts International, Volume: 81-03, Section: B.

Advisors: Smith, Amos B.; Committee members: Jeffrey Winkler; Donna Huryn; Gary Molander.

Department: Chemistry.

Ph.D. University of Pennsylvania 2019.

Local Notes:

School code: 0175

ISBN:

9781088365007

Access Restriction:

Restricted for use by site license.

This item is not available from ProQuest Dissertations & Theses.

This item must not be sold to any third party vendors.