Synthetic mimetics of actin-binding macrolides: rational design of actin-targeted drugs.
Actin polymerization and dynamics are involved in a wide range of cellular processes such as cell division and migration of tumor cells. At sites of cell lysis, such as those occurring during a stroke or inflammatory lung diseases, actin is released into the serum where it polymerizes, leading to problems with clot dissolution and sputum viscosity. Therefore, drugs that target these actin-mediated processes may provide one mechanism to treat these conditions. Marine-organism-derived macrolides, such as reidispongiolide A, can bind to, sever, and inhibit polymerization of actin. Our studies show that the function of these complex macrolides resides in their tail region, whereas the head group stabilizes the actin-drug complex. Synthetic compounds derived from this tail region could therefore be used as a mimetic of the natural product, providing a range of designer compounds to treat actin-associated diseases or as probes to study actin polymerization.
Perrins
Richard D
RD
Department of Physiology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
Cecere
Giuseppe
G
Paterson
Ian
I
Marriott
Gerard
G
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D007659:Ketones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D001743:Urinary Bladder / Q000166:cytology
D000199:Actins; D007659:Ketones; D018942:Macrolides; C476919:reidispongiolide A