Search

Nitric oxide (NO) is a widely distributed gasotransmitter binding to the heme of soluble guanylate cyclase (sGC) to stimulate the formation of the second messenger cyclic GMP. In disease, two pathomechanisms can occur, scavenging of NO by reactive oxygen species so that sGC is insufficiently stimulated, and oxidative damage of sGC resulting in heme loss and a NO-insensitive apo-form of sGC. To address this therapeutically, two pharmacological principles have entered the clinic or clinical development. sGC stimulators (sGCs) allosterically sensitize sGC for lower NO levels to reach physiological cGMP levels again; sGC activators (sGCa) bind to the empty heme pocket of apo-sGC to recover cGMP formation. Here we show in vitro and in vivo that this dichotomic pharmacology of sGCs/sGC and sGCa/apo-sGC is wrong. Instead apo-sGC is both activated by sGCa and allosterically modulated by sGC stimulators. The sGCs binding site in sGC and apo-sGC, however, is redox sensitive explaining why it has been previously missed in apo-sGC preparations generated for example by using heme oxidants such as 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Moreover, sGCs synergised with sGCa on apo-sGC in a supra-additive manner similar to the synergy between NO and sGCs on sGC. Our findings provide functional evidence including ischemic stroke, where apo-sGC rather than sGC is detectable, for identical modulation of sGC and apo-sGC by sGCs. This necessitates a revision of the dichotomic sGC/apo-sGC pharmacology and expands the therapeutic potential of sGCs and sGCa both individually and in combination.

Noncommunicable diseases (NCDs) have become globally abundant, yet the therapeutics we use for them are imprecise. In parallel, identifying new treatments has become more costly than ever due to the ever-aggravating efficacy crisis drug discovery faces. What unites these failures is our ontological classification of diseases, primarily based on descriptive terms. To achieve precision diagnosis and precision therapy in clinical practice, NCDs need to be redefined and subdivided based on their causal molecular mechanisms. However, the inconsistency and incompatibility of the current disease classification systems hinder data integration and analysis towards the characterization of such mechanisms. Here, we explain flaws in the current disease definitions and the dispersion among existing ontologies with the aim of establishing a mechanism-based classification of diseases hence, precision medicine.

Nitric oxide (NO) is a widely distributed gasotransmitter binding to the heme of soluble guanylate cyclase (sGC) to stimulate the formation of the second messenger cyclic GMP. In disease, two pathomechanisms can occur, scavenging of NO by reactive oxygen species so that sGC is insufficiently stimulated, and oxidative damage of sGC resulting in heme loss and a NO-insensitive apo-form of sGC. To address this therapeutically, two pharmacological principles have entered the clinic or clinical development. sGC stimulators (sGCs) allosterically sensitize sGC for lower NO levels to reach physiological cGMP levels again; sGC activators (sGCa) bind to the empty heme pocket of apo-sGC to recover cGMP formation. Here we show in vitro and in vivo that this dichotomic pharmacology of sGCs/sGC and sGCa/apo-sGC is wrong. Instead apo-sGC is both activated by sGCa and allosterically modulated by sGC stimulators. The sGCs binding site in sGC and apo-sGC, however, is redox sensitive explaining why it has been previously missed in apo-sGC preparations generated for example by using heme oxidants such as 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Moreover, sGCs synergised with sGCa on apo-sGC in a supra-additive manner similar to the synergy between NO and sGCs on sGC. Our findings provide functional evidence including ischemic stroke, where apo-sGC rather than sGC is detectable, for identical modulation of sGC and apo-sGC by sGCs. This necessitates a revision of the dichotomic sGC/apo-sGC pharmacology and expands the therapeutic potential of sGCs and sGCa both individually and in combination.