Small-Molecule Antibody Recruiting Therapeutics for Treating Human Disease

点击翻译按钮获取中文摘要

In recent years, antibody-based therapeutics have become important instruments in treating human diseases ranging from rheumatoid arthritis to cancer. However, these approaches suffer from certain limitations including severe (often fatal) side-effects, lack of oral bioavailability, and high cost. Here, we propose an alternative method that exploits the powerful cytolytic potential of antibodies already present in the human bloodstream. We will synthesize small-molecules capable of redirecting endogenous anti-2,4-dinitrophenyl (anti-DNP) antibodies to the surfaces of various pathogenic cell-types (Figure). As shown, bifunctional molecular constructs will be composed of a bivalent antibody-binding terminus (ABT), a cell surfacebinding terminus (CBT), and a linker region. Formation of a ternary complex between these agents, anti-DNP antibodies, and target cells, will lead to targeted cytotoxicity through various mechanisms including antibody-dependent cellular cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC). Applications of this approach to cancer and HIV treatment are described, along with more general directions. The proposed studies involve three aims: (1) to synthesize and evaluate an ABT capable of binding endogenous anti-DNP antibodies with high affinity, (2) to synthesize and evaluate a bifunctional small-molecule antiviral reagent targeting HIV gp120, and (3) to identify a small-molecule ligand for the interleukin-6 (IL-6) receptor for incorporation into bifunctional therapeutics targeting the B-cell malignancy multiple myeloma. Concise chemical syntheses of these agents are set forth, and encompass no more than six chemical transformations each. Biological evaluation will employ well established in vitro, and tissue culture models. Mathematical modeling studies are also reported that demonstrate numerically the feasibility of this approach for in vivo applications. Since high-throughput screening methods are ideally suited to identifying cell surface binding small-molecules, this general strategy is not limited to any particular type of target cell. If successful, the proposed method would represent a novel therapeutic approach to a variety of human diseases.