Glucosepane Crosslink Breakers: Necessity and Prospects
J.D. Furber
Legendary Pharmaceuticals, PO Box 14200, Gainesville, FL 32604-2200, USA
Extracellular aging -- accumulating molecular damage by glycation,
oxidation, and crosslinking of long-lived extracellular proteins,
mainly collagen and elastin -- is a major cause of several important
human aging pathologies. Crosslinking increases mechanical stiffness
of blood vessels and urinary bladder. Crosslinking impairs functioning
of kidney, heart, retina, and other tissues and organs. Glycation
adducts trigger inflammatory signaling, provoking tissue damage and
cancers. Crosslinking tightens up the extracellular matrix (ECM),
hardening it against natural turnover processes. Known crosslink
breakers (eg. alagebrium, of the thiazolium halide family) are only
partly effective because they break only a subset of AGE crosslink
structures (sugar-derived alpha-diketone bridges). So far, no agent
has been found which breaks the more prevalent glucosepane crosslink
structures. Enzymes which are able to recognize and disassemble
glycation products are too big to migrate into the ECM and repair
collagen or elastin in vivo. Two approaches to therapy
development are presented: ECM Turnover Stimulation would
activate or enhance natural processes to digest old ECM and replace it
with new. It will be important to tune the collagen degradation to a
rate slow enough to prevent dire side effects, such as hemorrhage from
leaky blood vessels as collagen molecules are removed and replaced.
Glucosepane Breaker Discovery would use rational drug design and
high-throughput screening to find small molecules which are able to
break glucosepane crosslinks of extracellular proteins. Candidates
would be further screened for selectivity in order to ensure that only
glucosepane gets broken.
Key words:
crosslinks, extracellular, glucosepane, collagen, turnover
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