New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production

Lactate dehydrogenase A inhibitors with a 2,8-dioxabicyclo[3.3.1]nonane scaffold: A contribution to molecular therapies for primary hyperoxalurias

“…The hypothesis of double GO/LDHA inhibition leading to more effective and safe drugs has been introduced [5,9,22]. Díaz-Gavilán and col. bet on using the same pharmacophore with a salicylic acid core against both enzymes [22].…”

“…The hypothesis of double GO/LDHA inhibition leading to more effective and safe drugs has been introduced [5,9,22]. Díaz-Gavilán and col. bet on using the same pharmacophore with a salicylic acid core against both enzymes [22]. Likewise, Lowther and col. have synthesized and evaluated compounds whose structures result from the merger of two scaffolds, one of them is present in a reported GOi and the other one in LDHA inhibitors (LDHAi's) [23].…”

Improving Treatment Options for Primary Hyperoxaluria

“…If both RNAi medications fail singularly, combined administration of GO and LDHA blockers may be considered. Examples are the PH1 infant treated with lumasiran and stiripentol [ 85 ] (a small molecule that inhibits LDHA, see below) (Table 1 ), and new small molecules that inhibit both GO and LDHA enzymes, showing efficacy in primary hepatocytes from all PH animal models (1–3) [ 96 , 97 ]. If these all fail, patients must remain on standard treatment of care and a close follow-up evaluation of the disease course.…”

Molecular Mechanisms, Genotype–Phenotype Correlations and Patient-Specific Treatments in Inherited Metabolic Diseases

“…This is a consequence of the propagation of local stability effects across the protein structure [ 11 , 13 , 14 , 15 , 16 , 17 , 18 ] ( Figure 1 ). In this Special Issue, we focus on three critical aspects currently under development regarding metabolic diseases with a genetic origin, namely the high-throughput computation of genotype–phenotype correlations [ 19 ], their treatment using natural or pharmacological chaperones [ 20 , 21 ] and the inhibition of altered metabolic routes to prevent the accumulation of toxic intermediates [ 22 ].…”

“…More recently, the same group have described the successful development of pharmacological chaperones that partially restore the normal AGT activity of PH1-causing mutations [ 25 ]. Moya-Garzón and coworkers present in this Special Issue an alternative for the treatment of PH1 based on inhibitors of oxalate formation that is currently under further development by using tools from medicinal chemistry [ 22 , 26 ]. Human galactose 1-phosphate uridylyltransferase (GALT) is also a dimeric protein involved in the metabolism of galactose, and whose deficiency due to inherited mutations leads to galactosemia type I (GT1) [ 27 ].…”