Feryel Soualmia - Academia.edu (original) (raw)

Papers by Feryel Soualmia

bioRxiv, 2021

Caspase-2 (Casp2) is a promising therapeutic target in several human diseases including nonalcoho... more Caspase-2 (Casp2) is a promising therapeutic target in several human diseases including nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease (AD). However, the design of active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extremely similar active sites. Here we present new peptidomimetics derived from the VDVAD pentapeptide structure, harboring non-natural modifications at the P2 position and an irreversible warhead. Enzyme kinetics shows that these new compounds, such as LJ2 or its specific isomer LJ2a, and LJ3a, strongly and irreversibly inhibit Casp2 with genuine selectivity. According to Casp2 role in cellular stress responses, LJ2 inhibits cell death induced by microtubule destabilization or hydroxamic acid-based deacetylase inhibition. The most potent peptidomimetic, LJ2a, inhibits human Casp2 with a remarkably high inactivation rate (k3/Ki ~ 5 500 000 M−1s−1) and the most selective inhibitor, LJ3a, has a ne...

European Journal of Medicinal Chemistry, 2015

The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrei... more The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family. KLK7 is involved in skin homeostasis and inflammation. Excess of KLK7 activity is also associated with tumor metastasis processes, especially in ovarian carcinomas, prostatic and pancreatic cancers. Development of Kallikrein 7 inhibitors is thus of great interest in oncology but also for treating skin diseases. Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chemical properties for in vivo use. Recently, we described a practical sequence for the synthesis of imidazopyridinefused [1,3]-diazepines. Here, we report the identification of pyridoimidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7. Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.

Biomolecules

Kallikrein-related peptidases (KLKs) are implicated in many cancer-related processes. KLK6, one o... more Kallikrein-related peptidases (KLKs) are implicated in many cancer-related processes. KLK6, one of the 15 KLK family members, is a promising biomarker for diagnosis of many cancers and has been associated with poor prognosis of colorectal cancer (CRC) patients. Herein, we evaluated the expression and cellular functions of KLK6 in colon cancer-derived cell lines and in clinical samples from CRC patients. We showed that, although many KLKs transcripts are upregulated in colon cancer-derived cell lines, KLK6, KLK10, and KLK11 are the most highly secreted proteins. KLK6 induced calcium flux in HT29 cells by activation and internalization of protease-activated receptor 2 (PAR2). Furthermore, KLK6 induced extracellular signal–regulated kinases 1 and 2 (ERK1/2) phosphorylation. KLK6 suppression in HCT-116 colon cancer cells decreased the colony formation, increased cell adhesion to extracellular matrix proteins, and reduced spheroid formation and compaction. Immunohistochemistry (IHC) anal...

Chemistry: A European Journal, Mar 7, 2022

B12 -dependent radical SAM enzymes are an emerging enzyme family with approximately 200,000 prote... more B12 -dependent radical SAM enzymes are an emerging enzyme family with approximately 200,000 proteins. These enzymes have been shown to catalyze chemically challenging reactions such as methyl transfer to sp2- and sp3-hybridized carbon atoms. However, to date we have little information regarding their complex mechanisms and their biosynthetic potential. Here we show, using X-ray absorption spectroscopy, mutagenesis and synthetic probes that the vitamin B12 -dependent radical SAM enzyme TsrM catalyzes not only C- but also N-methyl transfer reactions further expanding its synthetic versatility. We also demonstrate that TsrM has the unique ability to directly transfer a methyl group to the benzyl core of tryptophan, including the least reactive position C4. Collectively, our study supports that TsrM catalyzes non-radical reactions and establishes the usefulness of radical SAM enzymes for novel biosynthetic schemes including serial alkylation reactions at particularly inert C-H bonds.

Correction to “Gold-Catalyzed Spirocyclization Reactions of N‑Propargyl Tryptamines and Tryptopha... more Correction to “Gold-Catalyzed Spirocyclization Reactions of N‑Propargyl Tryptamines and Tryptophans in Aqueous Media”

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS... more Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory, and cognitive impairments. Kallikrein-related peptidase (KLK)6 is the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes, the myelin-producing cells of the CNS, and KLK6 is assumed to be a robust biomarker of MS, since it is highly increased in the cerebrospinal fluid (CSF) of MS patients. Here, we report the design and biological evaluation of KLK6's low-molecular-weight inhibitors, para-aminobenzyl derivatives. Interestingly, selected hit compounds were selective of the KLK6 proteolytic network encompassing KLK1 and plasmin that also participate in the development of MS physiopathology. Moreover, hits were found noncytotoxic on primary cultures of murine neurons and oligodendrocyte precursor cells (OPCs). Among them, two compounds (32 and 42) were shown to promote the differentiation of OPCs into mature oligodendrocytes in vitro constituting thus emerging leads for the development of regenerative therapies.

N-Propargyl tryptamine and tryptophan derivatives that are readily available from both synthetic ... more N-Propargyl tryptamine and tryptophan derivatives that are readily available from both synthetic and biocatalytic approaches, undergo gold-catalyzed dearomative cyclizations in aqueous media to the corresponding spirocyclic derivatives. In addition to the efficiency of the method, operating in aqueous media affords a selective entry to C2-unsubstituted spiroindolenines that have long remained unattainable by Au(I)-catalysis. Moderate to excellent yields of the desired spirocyclic products bearing various substituents were obtained.

European Journal of Organic Chemistry

Expert opinion on therapeutic patents, 2018

Inflammation is a physiological part of the complex biological response of tissues to counteract ... more Inflammation is a physiological part of the complex biological response of tissues to counteract various harmful signals. This process involves diverse actors such as immune cells, blood vessels, and nerves as sources of mediators for inflammation control. Among them serine proteases are key elements in both physiological and pathological inflammation. Areas covered: Serine protease inhibitors to treat inflammatory diseases are being actively investigated by various industrial and academic institutions. The present review covers patent literature on serine protease inhibitors for the therapy of inflammatory diseases patented between 2011 and 2016. Expert opinion: Serine proteases regulating inflammation are versatile enzymes, usually involved in proinflammatory cytokine production and activation of immune cells. Their dysregulation during inflammation can have devastating consequences, promoting various diseases including skin and lung inflammation, neuroinflammation, and inflammato...

Biological chemistry, 2018

The activity of kallikrein-related peptidase 6 (KLK6) is deregulated in various diseases such as ... more The activity of kallikrein-related peptidase 6 (KLK6) is deregulated in various diseases such as cancer and neurodegenerative diseases. KLK6 is thus considered as an attractive therapeutical target. In this short report, we depict some novel findings on the regulation of the KLK6 activity. Namely, we identified mechanism-based inhibitors (suicide substrates) from an in-house library of 6-substituted coumarin-3-carboxylate derivatives. In addition, a molecular dynamics study evidenced the allosteric behavior of KLK6 similar to that previously observed for some trypsin-like serine proteases. This allosteric behavior together with the coumarinic scaffold bring new opportunities for the design of KLK6 potent activity modulators, useful as therapeutics or activity-based probes.

Journal of Medicinal Chemistry, 2015

Expert opinion on therapeutic patents, 2018

Inflammation is a physiological part of the complex biological response of tissues to counteract ... more Inflammation is a physiological part of the complex biological response of tissues to counteract various harmful signals. This process involves diverse actors such as immune cells, blood vessels, and nerves as sources of mediators for inflammation control. Among them serine proteases are key elements in both physiological and pathological inflammation. Areas covered: Serine protease inhibitors to treat inflammatory diseases are being actively investigated by various industrial and academic institutions. The present review covers patent literature on serine protease inhibitors for the therapy of inflammatory diseases patented between 2011 and 2016. Expert opinion: Serine proteases regulating inflammation are versatile enzymes, usually involved in proinflammatory cytokine production and activation of immune cells. Their dysregulation during inflammation can have devastating consequences, promoting various diseases including skin and lung inflammation, neuroinflammation, and inflammato...

Journal of Raman Spectroscopy, 2016

Journal of Medicinal Chemistry, 2015

The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates... more The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates the kallikrein proteolytic cascade) constitutes an innovative way to treat some skin diseases such as Netherton syndrome. We present here the inhibitory properties of coumarin-3carboxylate derivatives against these enzymes. Our small collection of these versatile organic compounds was enriched by newly synthesized derivatives in order to obtain molecules selective against one, two, three enzymes or acting on the four ones. We evidenced a series of compounds with IC 50 values in the nanomolar range. A suicide mechanism was observed against kallikrein 7 whereas the inactivation was either definitive (suicide type) or transient for kallikreins 5 and 14, and matriptase. Most of these potent inhibitors were devoid of cytotoxicity toward healthy human keratinocytes. In situ zymography investigations on skin sections from human kallikrein 5 transgenic mouse revealed significant reduction of the global proteolytic activity by several compounds. | J. Med. Chem. 2015, 58, 598−612 b Reagents: i: naphtol (2 equiv), OPCl 3 (2 equiv), 100°C, 90 min ii: salicylaldehyde (0.7 equiv), piperidine, HOAc, dioxane, r.t., 30 min.

European Journal of Medicinal Chemistry, 2015

The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrei... more The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family. KLK7 is involved in skin homeostasis and inflammation. Excess of KLK7 activity is also associated with tumor metastasis processes, especially in ovarian carcinomas, prostatic and pancreatic cancers. Development of Kallikrein 7 inhibitors is thus of great interest in oncology but also for treating skin diseases. Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chemical properties for in vivo use. Recently, we described a practical sequence for the synthesis of imidazopyridine-fused [1,3]-diazepines. Here, we report the identification of pyrido-imidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7. Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.

bioRxiv, 2021

Caspase-2 (Casp2) is a promising therapeutic target in several human diseases including nonalcoho... more Caspase-2 (Casp2) is a promising therapeutic target in several human diseases including nonalcoholic steatohepatitis (NASH) and Alzheimer’s disease (AD). However, the design of active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extremely similar active sites. Here we present new peptidomimetics derived from the VDVAD pentapeptide structure, harboring non-natural modifications at the P2 position and an irreversible warhead. Enzyme kinetics shows that these new compounds, such as LJ2 or its specific isomer LJ2a, and LJ3a, strongly and irreversibly inhibit Casp2 with genuine selectivity. According to Casp2 role in cellular stress responses, LJ2 inhibits cell death induced by microtubule destabilization or hydroxamic acid-based deacetylase inhibition. The most potent peptidomimetic, LJ2a, inhibits human Casp2 with a remarkably high inactivation rate (k3/Ki ~ 5 500 000 M−1s−1) and the most selective inhibitor, LJ3a, has a ne...

European Journal of Medicinal Chemistry, 2015

The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrei... more The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family. KLK7 is involved in skin homeostasis and inflammation. Excess of KLK7 activity is also associated with tumor metastasis processes, especially in ovarian carcinomas, prostatic and pancreatic cancers. Development of Kallikrein 7 inhibitors is thus of great interest in oncology but also for treating skin diseases. Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chemical properties for in vivo use. Recently, we described a practical sequence for the synthesis of imidazopyridinefused [1,3]-diazepines. Here, we report the identification of pyridoimidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7. Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.

Biomolecules

Kallikrein-related peptidases (KLKs) are implicated in many cancer-related processes. KLK6, one o... more Kallikrein-related peptidases (KLKs) are implicated in many cancer-related processes. KLK6, one of the 15 KLK family members, is a promising biomarker for diagnosis of many cancers and has been associated with poor prognosis of colorectal cancer (CRC) patients. Herein, we evaluated the expression and cellular functions of KLK6 in colon cancer-derived cell lines and in clinical samples from CRC patients. We showed that, although many KLKs transcripts are upregulated in colon cancer-derived cell lines, KLK6, KLK10, and KLK11 are the most highly secreted proteins. KLK6 induced calcium flux in HT29 cells by activation and internalization of protease-activated receptor 2 (PAR2). Furthermore, KLK6 induced extracellular signal–regulated kinases 1 and 2 (ERK1/2) phosphorylation. KLK6 suppression in HCT-116 colon cancer cells decreased the colony formation, increased cell adhesion to extracellular matrix proteins, and reduced spheroid formation and compaction. Immunohistochemistry (IHC) anal...

Chemistry: A European Journal, Mar 7, 2022

B12 -dependent radical SAM enzymes are an emerging enzyme family with approximately 200,000 prote... more B12 -dependent radical SAM enzymes are an emerging enzyme family with approximately 200,000 proteins. These enzymes have been shown to catalyze chemically challenging reactions such as methyl transfer to sp2- and sp3-hybridized carbon atoms. However, to date we have little information regarding their complex mechanisms and their biosynthetic potential. Here we show, using X-ray absorption spectroscopy, mutagenesis and synthetic probes that the vitamin B12 -dependent radical SAM enzyme TsrM catalyzes not only C- but also N-methyl transfer reactions further expanding its synthetic versatility. We also demonstrate that TsrM has the unique ability to directly transfer a methyl group to the benzyl core of tryptophan, including the least reactive position C4. Collectively, our study supports that TsrM catalyzes non-radical reactions and establishes the usefulness of radical SAM enzymes for novel biosynthetic schemes including serial alkylation reactions at particularly inert C-H bonds.

Correction to “Gold-Catalyzed Spirocyclization Reactions of N‑Propargyl Tryptamines and Tryptopha... more Correction to “Gold-Catalyzed Spirocyclization Reactions of N‑Propargyl Tryptamines and Tryptophans in Aqueous Media”

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS... more Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory, and cognitive impairments. Kallikrein-related peptidase (KLK)6 is the most abundant serine protease secreted in the CNS, mainly by oligodendrocytes, the myelin-producing cells of the CNS, and KLK6 is assumed to be a robust biomarker of MS, since it is highly increased in the cerebrospinal fluid (CSF) of MS patients. Here, we report the design and biological evaluation of KLK6's low-molecular-weight inhibitors, para-aminobenzyl derivatives. Interestingly, selected hit compounds were selective of the KLK6 proteolytic network encompassing KLK1 and plasmin that also participate in the development of MS physiopathology. Moreover, hits were found noncytotoxic on primary cultures of murine neurons and oligodendrocyte precursor cells (OPCs). Among them, two compounds (32 and 42) were shown to promote the differentiation of OPCs into mature oligodendrocytes in vitro constituting thus emerging leads for the development of regenerative therapies.

N-Propargyl tryptamine and tryptophan derivatives that are readily available from both synthetic ... more N-Propargyl tryptamine and tryptophan derivatives that are readily available from both synthetic and biocatalytic approaches, undergo gold-catalyzed dearomative cyclizations in aqueous media to the corresponding spirocyclic derivatives. In addition to the efficiency of the method, operating in aqueous media affords a selective entry to C2-unsubstituted spiroindolenines that have long remained unattainable by Au(I)-catalysis. Moderate to excellent yields of the desired spirocyclic products bearing various substituents were obtained.

European Journal of Organic Chemistry

Expert opinion on therapeutic patents, 2018

Inflammation is a physiological part of the complex biological response of tissues to counteract ... more Inflammation is a physiological part of the complex biological response of tissues to counteract various harmful signals. This process involves diverse actors such as immune cells, blood vessels, and nerves as sources of mediators for inflammation control. Among them serine proteases are key elements in both physiological and pathological inflammation. Areas covered: Serine protease inhibitors to treat inflammatory diseases are being actively investigated by various industrial and academic institutions. The present review covers patent literature on serine protease inhibitors for the therapy of inflammatory diseases patented between 2011 and 2016. Expert opinion: Serine proteases regulating inflammation are versatile enzymes, usually involved in proinflammatory cytokine production and activation of immune cells. Their dysregulation during inflammation can have devastating consequences, promoting various diseases including skin and lung inflammation, neuroinflammation, and inflammato...

Biological chemistry, 2018

The activity of kallikrein-related peptidase 6 (KLK6) is deregulated in various diseases such as ... more The activity of kallikrein-related peptidase 6 (KLK6) is deregulated in various diseases such as cancer and neurodegenerative diseases. KLK6 is thus considered as an attractive therapeutical target. In this short report, we depict some novel findings on the regulation of the KLK6 activity. Namely, we identified mechanism-based inhibitors (suicide substrates) from an in-house library of 6-substituted coumarin-3-carboxylate derivatives. In addition, a molecular dynamics study evidenced the allosteric behavior of KLK6 similar to that previously observed for some trypsin-like serine proteases. This allosteric behavior together with the coumarinic scaffold bring new opportunities for the design of KLK6 potent activity modulators, useful as therapeutics or activity-based probes.

Journal of Medicinal Chemistry, 2015

Expert opinion on therapeutic patents, 2018

Inflammation is a physiological part of the complex biological response of tissues to counteract ... more Inflammation is a physiological part of the complex biological response of tissues to counteract various harmful signals. This process involves diverse actors such as immune cells, blood vessels, and nerves as sources of mediators for inflammation control. Among them serine proteases are key elements in both physiological and pathological inflammation. Areas covered: Serine protease inhibitors to treat inflammatory diseases are being actively investigated by various industrial and academic institutions. The present review covers patent literature on serine protease inhibitors for the therapy of inflammatory diseases patented between 2011 and 2016. Expert opinion: Serine proteases regulating inflammation are versatile enzymes, usually involved in proinflammatory cytokine production and activation of immune cells. Their dysregulation during inflammation can have devastating consequences, promoting various diseases including skin and lung inflammation, neuroinflammation, and inflammato...

Journal of Raman Spectroscopy, 2016

Journal of Medicinal Chemistry, 2015

The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates... more The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates the kallikrein proteolytic cascade) constitutes an innovative way to treat some skin diseases such as Netherton syndrome. We present here the inhibitory properties of coumarin-3carboxylate derivatives against these enzymes. Our small collection of these versatile organic compounds was enriched by newly synthesized derivatives in order to obtain molecules selective against one, two, three enzymes or acting on the four ones. We evidenced a series of compounds with IC 50 values in the nanomolar range. A suicide mechanism was observed against kallikrein 7 whereas the inactivation was either definitive (suicide type) or transient for kallikreins 5 and 14, and matriptase. Most of these potent inhibitors were devoid of cytotoxicity toward healthy human keratinocytes. In situ zymography investigations on skin sections from human kallikrein 5 transgenic mouse revealed significant reduction of the global proteolytic activity by several compounds. | J. Med. Chem. 2015, 58, 598−612 b Reagents: i: naphtol (2 equiv), OPCl 3 (2 equiv), 100°C, 90 min ii: salicylaldehyde (0.7 equiv), piperidine, HOAc, dioxane, r.t., 30 min.

European Journal of Medicinal Chemistry, 2015

The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrei... more The human tissue kallikrein-7 (KLK7) is a chymotryptic serine protease member of tissue kallikrein family. KLK7 is involved in skin homeostasis and inflammation. Excess of KLK7 activity is also associated with tumor metastasis processes, especially in ovarian carcinomas, prostatic and pancreatic cancers. Development of Kallikrein 7 inhibitors is thus of great interest in oncology but also for treating skin diseases. Most of the developed synthetic inhibitors present several drawbacks such as poor selectivity and unsuitable physico-chemical properties for in vivo use. Recently, we described a practical sequence for the synthesis of imidazopyridine-fused [1,3]-diazepines. Here, we report the identification of pyrido-imidazodiazepinone core as a new potential scaffold to develop selective and competitive inhibitors of kallikrein-related peptidase 7. Structure-activity relationships (SAR), inhibition mechanisms and selectivity as well as cytotoxicity against selected cancer cell lines were investigated.