LFA-1 as a key regulator of immune function: approaches toward the development of LFA-1-based therapeutics.

Abstract:

:Over the past decade, Lymphocyte Function-Associated Antigen-1 (LFA-1, alphaLbeta2, CD11a/CD18) has emerged as an attractive therapeutic target for the treatment of multiple inflammatory diseases. Its established role in the trafficking and activation of leukocytes coupled with the recent elucidation of the global conformational changes that govern its function continue to drive pharmaceutical interest in this target. This sustained interest has led to the implementation of numerous drug discovery strategies leading to the development of antibodies, peptidomimetics, and small molecules that block LFA-1 function. The most successful demonstration of clinical efficacy to date has been with Raptiva, a humanized anti-LFA-1 antibody. In clinical trials of patients with moderate to severe psoriasis, improvements in several disease specific parameters including the Psoriasis Area and Severity Index (PASI) were observed. This review article will provide an overview of LFA-1 biology and structural regulation, as well as strategies that have been adopted in pursuit of effective therapies. Recent findings with different classes of small molecule antagonists will be highlighted with an emphasis on how their different mechanisms of action on the inserted domain (I domain) of CD11a have impacted our understanding of LFA-1 function and illuminated other potential avenues for therapeutic intervention.

journal_name

Curr Pharm Des

authors

Giblin PA,Lemieux RM

doi

10.2174/138161206777947731

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

2771-95

issue

22

eissn

1381-6128

issn

1873-4286

journal_volume

12

pub_type

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