Design, synthesis, and optimization of cd4-mimetic small molecules entry inhibitor targeting hiv-1_gp120 Ta-Jung Darren Chiu

Format:

Book

Thesis/Dissertation

Author/Creator:

Chiu, Ta-Jung Darren, author.

Contributor:

University of Pennsylvania. Chemistry., degree granting institution.

Language:

English

Subjects (All):

Organic chemistry.

Pharmacology.

Biochemistry.

Virology.

0490.

0720.

0487.

0419.

Local Subjects:

Organic chemistry.

Pharmacology.

Biochemistry.

Virology.

0490.

0720.

0487.

0419.

Genre:

Academic theses

Physical Description:

1 online resource (382 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

The human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), has remained a serious global health crisis for over 40 years, with approximately 37.7 million people currently living with the disease. While highly active antiretroviral therapy (HAART) has transformed clinical outcomes, it remains limited by its inability to achieve total viral eradication, as well as challenges regarding cost, long-term toxicity, and the emergence of drug resistance. Consequently, the development of novel therapeutic strategies to address these limitations is essential. One promising approach involves CD4 mimetic compounds (CD4mcs), a class of small molecules designed to mimic the host T cell's CD4 receptor by binding specifically to the HIV envelope glycoprotein (Env). During HIV entry, the gp120/gp41 trimer on the viral surface typically engages the host T cell's CD4 receptor, followed by coreceptors CCR5 or CXCR4 to initiate membrane fusion with target T cells. CD4mcs exploit this mechanism by binding to the highly conserved CD4-binding site Phe43 cavity on the gp120, triggering a premature and irreversible conformational change. This forced transition locks Env into a more open and stabilized state, making the virus highly susceptible to antibody-dependent cellular cytotoxicity (ADCC) and resulting in effective neutralization. Chapter 2 details a 13-step optimized and scalable synthesis of the previously reported lead CD4mc, CJF-III-288. Chapters 3, 4, and 6 present the structure-activity relationship (SAR) studies of the indoline-based CD4mcs. These studies focus on modification at the N1, C4, and C6 positions, guided by X-ray crystallography and in vitro assays. Chapter 5 discusses the rationale, design, and synthesis of di-substituted indoline CD4mcs. The design of this scaffold was guided by the cumulative SAR results from the N1, C4, and C6 positions. By utilizing a novel synthetic route that reaches a common intermediate in 10 steps, this scaffold maintains the flexibility for late-stage functionalization at the N1 position while preserving the C6 methylaminomethyl side chain, which interacts with the nearby glycine (Gly) loop. In addition to these key features, the newly introduced C4 functionality offers the potential to engage the Asp368 residue, a critical component of the native CD4-gp120 binding interface. Through the development of this highly substituted indoline scaffold, we aim to produce CD4mcs capable of multi-residue engagement with gp120, thereby enhancing antiviral potency and expanding their potential therapeutic applications

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Walsh, Patrick J.; Huryn, Donna M.; Smith, Amos B., III Committee members: Chenoweth, David M.; Zahrt, Andrew; Booker, Squire J.

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247979715

Access Restriction:

Restricted for use by site license