1. ¹Archemix Corporation, Cambridge, MA, USA
2. ²Alnylam Pharmaceuticals, Cambridge, MA, USA

Correspondence: Dr EB De Souza, Archemix Corporation, 300 Third Street, Cambridge, MA 02142, USA. Tel: +1 617 475 2385; Fax: +1 617 621 9300; E-mail: edesouza@archemix.com

Received 18 April 2008; Revised 21 June 2008; Accepted 28 June 2008; Published online 27 August 2008.

Abstract

Small molecule drugs are relatively effective in working on 'drugable' targets such as GPCRs, ion channels, kinases, proteases, etc but ineffective at blocking protein–protein interactions that represent an emerging class of 'nondrugable' central nervous system (CNS) targets. This article provides an overview of novel therapeutic modalities such as biologics (in particular antibodies) and emerging oligonucleotide therapeutics such as antisense, small-interfering RNA, and aptamers. Their key properties, overall strengths and limitations, and their utility as tools for target validation are presented. In addition, issues with regard to CNS targets as it relates to the blood–brain barrier penetration are discussed. Finally, examples of their application as therapeutics for the treatment of pain and some neurological disorders such as Alzheimer's disease, multiple sclerosis, Huntington's disease, and Parkinson's disease are provided.