Insulin-Like Growth Factor System in HIV/AIDS: A Structure Based Approach to the Design of New Therapeutics

摘要: One of the important regulators for growth and development human body is endocrine system. The system composed glands that secrete hormones into circulatory system, which are then distributed throughout body, regulating function tissues maintaining homeostasis. Among these insulin-like factors (IGF), similar in molecular structure to insulin playing an role cell growth, proliferation, differentiation (LeRoith & Roberts, 2003). A complex network molecules, including its binding proteins, proteases receptors, together comprise ‘IGF system’, modulates biological IGFs. This comprises following components (Figure 1): (i) Two peptide hormones, IGF-1 2, (ii) type 1 2 IGF (iii) six IGF-binding proteins (IGFBP; numbered 1-6) (iv) IGFBP proteases. -2 small signalling peptides (~7.5 kDa) stimulate action by specific surface receptors (IGF-1R) evoking subsequent response inside cell. Six soluble IGFBPs, range size from 22-31 kDa share overall sequence structural homology with each other, regulate activity IGFBPs bind strongly IGFs (KD ~ 300-700 pM) ensure majority circulating blood stream sequestered at tissue level inhibit blocking their access receptors. Proteolysis dissociates complex, enabling them activate 1). In tissues, form a binary whereas associated ternary complexes containing IGFBP-3 (and IGFBP-5) third protein known as acid-labile subunit (ALS). has mass 150 kDa. most abundant IGFbinding circulation followed IGFBP-2. recent years, general particular have become focus clinically targets cancer therapeutics (Chan et al., 1998; Harrison 1996; LeRoith 2003; Ma 1999; Rosenzweig Atreya, 2010; Wu 2004; Yu 1999). Different strategies been proposed IGFI-R (recently reviewed (Rosenzweig 2010)). this regard, therapeutic potential inhibiting IGF-1/IGF-2 thereby demonstrated. Notably, do not thus interfere insulin-insulin receptor interactions.