Antonio Jiménez-Ruiz | Universidad de Alcala (original) (raw)

Papers by Antonio Jiménez-Ruiz

The execution of the apoptotic death program in metazoans is characterized by a sequence of morph... more The execution of the apoptotic death program in metazoans is characterized by a sequence of morphological and biochemical changes that include cell shrinkage, presentation of phosphatidylserine at the cell surface, mitochondrial alterations, chromatin condensation, nuclear fragmentation, membrane blebbing and the formation of apoptotic bodies. Methodologies for measuring apoptosis are based on these markers. Except for membrane blebbing and formation of apoptotic bodies, all other events have been observed in most protozoan parasites undergoing cell death. However, while techniques exist to detect these markers, they are often optimised for metazoan cells and therefore may not pick up subtle differences between the events occurring in unicellular organisms and multicellular organisms. In this review we discuss the markers most frequently used to analyze cell death in protozoan parasites, paying special attention to changes in cell morphology, mitochondrial activity, chromatin struct...

Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell ... more Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell death

Colombia Medica, 2011

Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishm... more Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishmania (Viannia) panamensis. Methods: The gene of the putative L. (V.) panamensis Endonuclease G was amplified, cloned, and sequenced. The recombinant protein was produced in a heterologous expression system and biochemical assays were run to determine its ion, temperature, and pH preferences. Results: The L. (V.) panamensis rENDOG has biochemical features similar to those found in other trypanosomatids and higher eukaryotes. In addition, phylogenetic analysis revealed a possible evolutionary relationship with metazoan ENDOG. Conclusions: L. (V.) panamensis has a gene that codifies an ENDOG homologous to those of higher organisms. This enzyme can be produced in Escherichia coli and is able to degrade covalently closed circular double-stranded DNA. It has a magnesium preference, can be inhibited by potassium, and is able to function within a wide temperature and pH range.

Ars Pharmaceutica, 1997

The primary structure of the PSA antigen from Leishmania infantum shows a high homology with Leis... more The primary structure of the PSA antigen from Leishmania infantum shows a high homology with Leishmania major PSA-2 antigen and Leishmania amazonensis GP46/M2 antigen. Aminoacid sequence analysis indicates that 60% of the molecule is formed by 13 repeated motives 24-25 aminoacids in length. The consensus sequence derived from these motives shows a highly significant homology with the consensus sequence described for leucine rich repeats, which indicates that L. infantum PSA, L. major PSA-2 and L. amazonensis GP46/M2 may be included into the newly described family of leucine rich repeat containing proteins. The expressed recombinant protein and several fragments expressed individually are efficiently recognized by sera from L. infantum naturally infected dogs and leishmaniasic human patients.

Colombia …, 2011

Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishm... more Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishmania (Viannia) panamensis. Methods: The gene of the putative L. (V.) panamensis Endonuclease G was amplified, cloned, and sequenced. The recombinant protein was produced in a heterologous expression system and biochemical assays were run to determine its ion, temperature, and pH preferences. Results: The L. (V.) panamensis rENDOG has biochemical features similar to those found in other trypanosomatids and higher eukaryotes. In addition, phylogenetic analysis revealed a possible evolutionary relationship with metazoan ENDOG. Conclusions: L. (V.) panamensis has a gene that codifies an ENDOG homologous to those of higher organisms. This enzyme can be produced in Escherichia coli and is able to degrade covalently closed circular double-stranded DNA. It has a magnesium preference, can be inhibited by potassium, and is able to function within a wide temperature and pH range.

Nucleic Acids Research, 1988

Molecular and Biochemical Parasitology, 1992

In the present paper we report the characterization of a repetitive DNA sequence from the genome ... more In the present paper we report the characterization of a repetitive DNA sequence from the genome of the Maracay strain of Trypanosoma cruzi. The sequence is 1025 nucleotides long and represent about 7% of the total nuclear DNA of the parasite with a copy number of 1-2 x 10(4) copies per genome. It is also present in a high copy number in several strains of T. cruzi but absent from other trypanosomatids and from the human genome. The DNA sequence is interspersed and present on many chromosomes. We show that the different copies of this repeat present extensive endonuclease restriction polymorphisms. Using 2 conserved oligonucleotide primers derived from the repetitive sequence, together with the polymerase chain reaction technique, the presence of less than 1/30 of a single parasite can be readily detected by ethidium bromide staining.

Molecular and Biochemical Parasitology, 1992

The steady-state level of the hsp70 mRNAs of Trypanosoma cruzi cultured at different temperatures... more The steady-state level of the hsp70 mRNAs of Trypanosoma cruzi cultured at different temperatures and growth conditions has been analyzed by Northern blotting. We show that only one size class of hsp70 mRNA, of about 2.2 kb, is transcribed from the hsp70 cluster and that its transcription is constitutive at 28°C. However, after a heat shock treatment at 37°C for 2 h of logarithmically growing parasites, the abundance of the hsp70 mRNA increased about 4-fold. A similar increase was observed at 28~'C when the parasite culture reached the stationary phase of growth. On the other hand, a heat shock at 42°C did not change the steady state level of the 2.2-kb size class of hsp70 mRNA. However, accumulation of transcripts of high molecular weight was detected when stationary growing parasites were cultured at 42°C for 2 h. Also at 37°C the steady state level of the a-and [/-tubulin mRNAs of logarithmically growing parasites exhibited a slight increase but only after a period of 24 h. Analysis by one-dimensional immunoblots of the Hsp70 levels showed that at 37°C the abundance of the protein was 4fold higher than at 28°C. lmmunoblots of high-resolution two-dimensional gel electrophoresis showed, moreover, that various isoforms of this protein are constitutively expressed at 28~C and that some of them have a specific pattern of induction at 37°C. We observed, moreover, that the heat, shock induces the expression of a series of proteins while it causes repression of others.

Biochemical and Biophysical Research Communications, 2003

SELEX procedure is a methodology in which single stranded oligonucleotides are selected from a wi... more SELEX procedure is a methodology in which single stranded oligonucleotides are selected from a wide variety of sequences based on their interaction with a target molecule. We have designed a novel SELEX methodology using colloidal gold to select high affinity single stranded DNA aptamers against Leishmania infantum KMP-11. Kinetoplastid membrane protein-11 (KMP-11) is a major component of the cell membrane of kinetoplastid parasites. Although its function is not known, the fact that KMP-11 is a cytoskeleton-associated protein suggests that it may be involved in mobility or in some other aspects of the flagellar structure. We have isolated a single stranded DNA aptamer population that binds specifically to L. infantum KMP-11. This population has been characterized in a series of in vitro experiments suggesting that it may be used as a powerful tool to further investigate the role of KMP-11 during Leishmania development and/or as a diagnostic tool in Leishmania infection.

ACS Infectious Diseases, 2019

Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules rep... more Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules represents a significant challenge. We recently reported some linear and cyclic peptides derived from an α-helical region present in the homodimeric interface of Leishmania infantum trypanothione reductase (Li-TryR) that showed potent effects on both dimerization and redox activity of this essential enzyme. Here we describe our first steps towards the design of non-peptidic small-molecule Li-TryR dimerization disruptors using a proteomimetic approach. The pyrrolopyrimidine and the 5-6-5 imidazole-phenyl-thiazole α-helix-mimetic scaffolds were suitably decorated with substituents that could mimic three key residues (K, Q and I) of the linear peptide prototype (PKIIQSVGIS-Nle-K-Nle). Extensive optimization of previously described synthetic methodologies was required. A library of 15 compounds bearing different hydrophobic alkyl and aromatic substituents was synthesized. The imidazole-phenyl-thiazole-based analogues outperformed the pyrrolopyrimidine-based derivatives in both inhibiting the enzyme and killing extracellular and intracellular parasites in cell culture. The most active imidazole-phenyl-thiazole compounds 3e and 3f inhibit Li-TryR and prevent growth of the parasites at low micromolar concentrations similar to those required by the peptide prototype. The intrinsic fluorescence of these compounds inside the parasites visually demonstrates their good permeability in comparison with previous peptide-based Li-TryR dimerization disruptors.

Journal of Biological Chemistry, 1995

Nucleic Acids Research, 1989

The hsp7O coding DNA of Trypanosoma cruzi is formed by multigene copies organized as a tandem arr... more The hsp7O coding DNA of Trypanosoma cruzi is formed by multigene copies organized as a tandem array in a head to tail manner (1). We have reported the partial sequence of one of these repeats. Here we describe the complete sequence of the same repeat containing the protein coding and the intergenic regions.The repeat is formed by 2494 nucleotides.At aminoacid level the homology with the hsp70 of T. brucei is 88% (2). However, the hsp7O of T. cruzi is 19 aminoacids longer than the hsp7o of T. brucei. The sequences containing the putative HSE goes from nucleotide 161-203, TATA box from 221-226, splicing acceptor from 247-251 and polyadenilation signal from 2470-2480. This work was supported by CICYT grants n.

European Journal of Medicinal Chemistry

European journal of medicinal chemistry, Jan 17, 2018

A series of new azolopyrimidine-peptide hybrids and indolomethylideneimidazolones were obtained a... more A series of new azolopyrimidine-peptide hybrids and indolomethylideneimidazolones were obtained and evaluated as calpain inhibitors. The hybrid compounds were inactive, whereas some members of the initial azolomethylideneimidazolone series showed interesting calpain inhibitory activity. By using 4b as a hit compound, a new series of analogs were synthesized by an efficient synthetic procedure based on a multicomponent reaction followed by an unprecedented reaction at the methylene position of the molecule. The best inhibitor found for calpain I (IC = 20 nM) was about 20 times more potent than the hit compound. Studies on 4b showed that its inhibition is consistent with an uncompetitive inhibition mode. This compound did not exhibit cellular toxicity at any of the doses tested (0.1-10 μM) and further studies indicated that it was capable of blockading chemical ischemia induction of apoptosis by preventing sodium azide-dependent calpain activation in intact human kidney tubular epithe...

Apoptosis, 2006

An increasing number of reports indicate that single-celled organisms are able to die following w... more An increasing number of reports indicate that single-celled organisms are able to die following what seems to be an ordered program of cell death with strong similarities to apoptosis from higher eukaryotes. DNA degradation and several other apoptotic-like processes have also been described in the parasitic protozoa Leishmania. However, the existence of an apoptotic death in this parasite is still a matter of controversy. Our results indicate that most of the processes of macromolecular degradation and organelle dysfunction observed in mammalian cells during apoptosis can also be reproduced in promastigotes of the genus Leishmania when incubated at temperatures above 38 degrees C. These processes can be partially reversed by the expression of the anti-apoptotic mammalian gene Bcl-X(L), which suggests that this family of apoptosis-regulating proteins was present very early in the evolution of eukaryotic cells.

PLOS ONE, 2014

<p>1 µg of supercoiled plasmid DNA (sc) was digested with increasing amounts of rLiEndoG (0... more <p>1 µg of supercoiled plasmid DNA (sc) was digested with increasing amounts of rLiEndoG (0, 20, 40, 80 and 160 ng) and with 160 ng of denatured rLiEndoG protein (160DP) as a negative control. The restriction enzyme Bgl II (Bgl II) was used as a control to generate linear DNA (lin). Each sample of digested DNA was split into two aliquots and one of them was heat-denatured (D) while the other one remained non-denatured (ND). All samples were electrophoresed in a 1% agarose gel and visualized under UV light. The different forms of plasmid DNA are indicated: open circular (oc); linear double-stranded (lin); supercoiled (sc); linear single-stranded (lin ss); circular single-stranded (cir ss).</p

European Journal of Medicinal Chemistry

European Journal of Medicinal Chemistry

Huntington’s disorder (HD) is one of the neurodegenerative disorders in which the polyglutamine (... more Huntington’s disorder (HD) is one of the neurodegenerative disorders in which the polyglutamine (polyQ) tract of the protein huntingtin (htt) is found to be expanded. First exon of this mutant htt protein is found in the inclusions in the brain of the patient suffering from HD, which is the pathological hallmark of the disease1. Exon-1 of htt comprises of 17 amino acid long N-terminal helix (Nt17), polyQ tract in between and polyP-rich C-terminal. Nt17 has been reported to selfassociate and enhance the rate of mutant htt aggregation which leads to protein aggregation resulting in the inclusion formation. The lysine residues K6 and K15 in Nt17 are thought to be involved in inter helical association and are proposed to form the template for initial oligomerization2. To prevent these specific residues from interacting, we have utilized a lysine specific molecular tweezer (MT) 3. Here, we have studied the effect of MT on the structure and oligomerization process of the mutant htt. By MD...

The execution of the apoptotic death program in metazoans is characterized by a sequence of morph... more The execution of the apoptotic death program in metazoans is characterized by a sequence of morphological and biochemical changes that include cell shrinkage, presentation of phosphatidylserine at the cell surface, mitochondrial alterations, chromatin condensation, nuclear fragmentation, membrane blebbing and the formation of apoptotic bodies. Methodologies for measuring apoptosis are based on these markers. Except for membrane blebbing and formation of apoptotic bodies, all other events have been observed in most protozoan parasites undergoing cell death. However, while techniques exist to detect these markers, they are often optimised for metazoan cells and therefore may not pick up subtle differences between the events occurring in unicellular organisms and multicellular organisms. In this review we discuss the markers most frequently used to analyze cell death in protozoan parasites, paying special attention to changes in cell morphology, mitochondrial activity, chromatin struct...

Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell ... more Targeting essential pathways in trypanosomatids gives insights into protozoan mechanisms of cell death

Colombia Medica, 2011

Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishm... more Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishmania (Viannia) panamensis. Methods: The gene of the putative L. (V.) panamensis Endonuclease G was amplified, cloned, and sequenced. The recombinant protein was produced in a heterologous expression system and biochemical assays were run to determine its ion, temperature, and pH preferences. Results: The L. (V.) panamensis rENDOG has biochemical features similar to those found in other trypanosomatids and higher eukaryotes. In addition, phylogenetic analysis revealed a possible evolutionary relationship with metazoan ENDOG. Conclusions: L. (V.) panamensis has a gene that codifies an ENDOG homologous to those of higher organisms. This enzyme can be produced in Escherichia coli and is able to degrade covalently closed circular double-stranded DNA. It has a magnesium preference, can be inhibited by potassium, and is able to function within a wide temperature and pH range.

Ars Pharmaceutica, 1997

The primary structure of the PSA antigen from Leishmania infantum shows a high homology with Leis... more The primary structure of the PSA antigen from Leishmania infantum shows a high homology with Leishmania major PSA-2 antigen and Leishmania amazonensis GP46/M2 antigen. Aminoacid sequence analysis indicates that 60% of the molecule is formed by 13 repeated motives 24-25 aminoacids in length. The consensus sequence derived from these motives shows a highly significant homology with the consensus sequence described for leucine rich repeats, which indicates that L. infantum PSA, L. major PSA-2 and L. amazonensis GP46/M2 may be included into the newly described family of leucine rich repeat containing proteins. The expressed recombinant protein and several fragments expressed individually are efficiently recognized by sera from L. infantum naturally infected dogs and leishmaniasic human patients.

Colombia …, 2011

Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishm... more Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishmania (Viannia) panamensis. Methods: The gene of the putative L. (V.) panamensis Endonuclease G was amplified, cloned, and sequenced. The recombinant protein was produced in a heterologous expression system and biochemical assays were run to determine its ion, temperature, and pH preferences. Results: The L. (V.) panamensis rENDOG has biochemical features similar to those found in other trypanosomatids and higher eukaryotes. In addition, phylogenetic analysis revealed a possible evolutionary relationship with metazoan ENDOG. Conclusions: L. (V.) panamensis has a gene that codifies an ENDOG homologous to those of higher organisms. This enzyme can be produced in Escherichia coli and is able to degrade covalently closed circular double-stranded DNA. It has a magnesium preference, can be inhibited by potassium, and is able to function within a wide temperature and pH range.

Nucleic Acids Research, 1988

Molecular and Biochemical Parasitology, 1992

In the present paper we report the characterization of a repetitive DNA sequence from the genome ... more In the present paper we report the characterization of a repetitive DNA sequence from the genome of the Maracay strain of Trypanosoma cruzi. The sequence is 1025 nucleotides long and represent about 7% of the total nuclear DNA of the parasite with a copy number of 1-2 x 10(4) copies per genome. It is also present in a high copy number in several strains of T. cruzi but absent from other trypanosomatids and from the human genome. The DNA sequence is interspersed and present on many chromosomes. We show that the different copies of this repeat present extensive endonuclease restriction polymorphisms. Using 2 conserved oligonucleotide primers derived from the repetitive sequence, together with the polymerase chain reaction technique, the presence of less than 1/30 of a single parasite can be readily detected by ethidium bromide staining.

Molecular and Biochemical Parasitology, 1992

The steady-state level of the hsp70 mRNAs of Trypanosoma cruzi cultured at different temperatures... more The steady-state level of the hsp70 mRNAs of Trypanosoma cruzi cultured at different temperatures and growth conditions has been analyzed by Northern blotting. We show that only one size class of hsp70 mRNA, of about 2.2 kb, is transcribed from the hsp70 cluster and that its transcription is constitutive at 28°C. However, after a heat shock treatment at 37°C for 2 h of logarithmically growing parasites, the abundance of the hsp70 mRNA increased about 4-fold. A similar increase was observed at 28~'C when the parasite culture reached the stationary phase of growth. On the other hand, a heat shock at 42°C did not change the steady state level of the 2.2-kb size class of hsp70 mRNA. However, accumulation of transcripts of high molecular weight was detected when stationary growing parasites were cultured at 42°C for 2 h. Also at 37°C the steady state level of the a-and [/-tubulin mRNAs of logarithmically growing parasites exhibited a slight increase but only after a period of 24 h. Analysis by one-dimensional immunoblots of the Hsp70 levels showed that at 37°C the abundance of the protein was 4fold higher than at 28°C. lmmunoblots of high-resolution two-dimensional gel electrophoresis showed, moreover, that various isoforms of this protein are constitutively expressed at 28~C and that some of them have a specific pattern of induction at 37°C. We observed, moreover, that the heat, shock induces the expression of a series of proteins while it causes repression of others.

Biochemical and Biophysical Research Communications, 2003

SELEX procedure is a methodology in which single stranded oligonucleotides are selected from a wi... more SELEX procedure is a methodology in which single stranded oligonucleotides are selected from a wide variety of sequences based on their interaction with a target molecule. We have designed a novel SELEX methodology using colloidal gold to select high affinity single stranded DNA aptamers against Leishmania infantum KMP-11. Kinetoplastid membrane protein-11 (KMP-11) is a major component of the cell membrane of kinetoplastid parasites. Although its function is not known, the fact that KMP-11 is a cytoskeleton-associated protein suggests that it may be involved in mobility or in some other aspects of the flagellar structure. We have isolated a single stranded DNA aptamer population that binds specifically to L. infantum KMP-11. This population has been characterized in a series of in vitro experiments suggesting that it may be used as a powerful tool to further investigate the role of KMP-11 during Leishmania development and/or as a diagnostic tool in Leishmania infection.

ACS Infectious Diseases, 2019

Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules rep... more Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules represents a significant challenge. We recently reported some linear and cyclic peptides derived from an α-helical region present in the homodimeric interface of Leishmania infantum trypanothione reductase (Li-TryR) that showed potent effects on both dimerization and redox activity of this essential enzyme. Here we describe our first steps towards the design of non-peptidic small-molecule Li-TryR dimerization disruptors using a proteomimetic approach. The pyrrolopyrimidine and the 5-6-5 imidazole-phenyl-thiazole α-helix-mimetic scaffolds were suitably decorated with substituents that could mimic three key residues (K, Q and I) of the linear peptide prototype (PKIIQSVGIS-Nle-K-Nle). Extensive optimization of previously described synthetic methodologies was required. A library of 15 compounds bearing different hydrophobic alkyl and aromatic substituents was synthesized. The imidazole-phenyl-thiazole-based analogues outperformed the pyrrolopyrimidine-based derivatives in both inhibiting the enzyme and killing extracellular and intracellular parasites in cell culture. The most active imidazole-phenyl-thiazole compounds 3e and 3f inhibit Li-TryR and prevent growth of the parasites at low micromolar concentrations similar to those required by the peptide prototype. The intrinsic fluorescence of these compounds inside the parasites visually demonstrates their good permeability in comparison with previous peptide-based Li-TryR dimerization disruptors.

Journal of Biological Chemistry, 1995

Nucleic Acids Research, 1989

The hsp7O coding DNA of Trypanosoma cruzi is formed by multigene copies organized as a tandem arr... more The hsp7O coding DNA of Trypanosoma cruzi is formed by multigene copies organized as a tandem array in a head to tail manner (1). We have reported the partial sequence of one of these repeats. Here we describe the complete sequence of the same repeat containing the protein coding and the intergenic regions.The repeat is formed by 2494 nucleotides.At aminoacid level the homology with the hsp70 of T. brucei is 88% (2). However, the hsp7O of T. cruzi is 19 aminoacids longer than the hsp7o of T. brucei. The sequences containing the putative HSE goes from nucleotide 161-203, TATA box from 221-226, splicing acceptor from 247-251 and polyadenilation signal from 2470-2480. This work was supported by CICYT grants n.

European Journal of Medicinal Chemistry

European journal of medicinal chemistry, Jan 17, 2018

A series of new azolopyrimidine-peptide hybrids and indolomethylideneimidazolones were obtained a... more A series of new azolopyrimidine-peptide hybrids and indolomethylideneimidazolones were obtained and evaluated as calpain inhibitors. The hybrid compounds were inactive, whereas some members of the initial azolomethylideneimidazolone series showed interesting calpain inhibitory activity. By using 4b as a hit compound, a new series of analogs were synthesized by an efficient synthetic procedure based on a multicomponent reaction followed by an unprecedented reaction at the methylene position of the molecule. The best inhibitor found for calpain I (IC = 20 nM) was about 20 times more potent than the hit compound. Studies on 4b showed that its inhibition is consistent with an uncompetitive inhibition mode. This compound did not exhibit cellular toxicity at any of the doses tested (0.1-10 μM) and further studies indicated that it was capable of blockading chemical ischemia induction of apoptosis by preventing sodium azide-dependent calpain activation in intact human kidney tubular epithe...

Apoptosis, 2006

An increasing number of reports indicate that single-celled organisms are able to die following w... more An increasing number of reports indicate that single-celled organisms are able to die following what seems to be an ordered program of cell death with strong similarities to apoptosis from higher eukaryotes. DNA degradation and several other apoptotic-like processes have also been described in the parasitic protozoa Leishmania. However, the existence of an apoptotic death in this parasite is still a matter of controversy. Our results indicate that most of the processes of macromolecular degradation and organelle dysfunction observed in mammalian cells during apoptosis can also be reproduced in promastigotes of the genus Leishmania when incubated at temperatures above 38 degrees C. These processes can be partially reversed by the expression of the anti-apoptotic mammalian gene Bcl-X(L), which suggests that this family of apoptosis-regulating proteins was present very early in the evolution of eukaryotic cells.

PLOS ONE, 2014

<p>1 µg of supercoiled plasmid DNA (sc) was digested with increasing amounts of rLiEndoG (0... more <p>1 µg of supercoiled plasmid DNA (sc) was digested with increasing amounts of rLiEndoG (0, 20, 40, 80 and 160 ng) and with 160 ng of denatured rLiEndoG protein (160DP) as a negative control. The restriction enzyme Bgl II (Bgl II) was used as a control to generate linear DNA (lin). Each sample of digested DNA was split into two aliquots and one of them was heat-denatured (D) while the other one remained non-denatured (ND). All samples were electrophoresed in a 1% agarose gel and visualized under UV light. The different forms of plasmid DNA are indicated: open circular (oc); linear double-stranded (lin); supercoiled (sc); linear single-stranded (lin ss); circular single-stranded (cir ss).</p

European Journal of Medicinal Chemistry

European Journal of Medicinal Chemistry

Huntington’s disorder (HD) is one of the neurodegenerative disorders in which the polyglutamine (... more Huntington’s disorder (HD) is one of the neurodegenerative disorders in which the polyglutamine (polyQ) tract of the protein huntingtin (htt) is found to be expanded. First exon of this mutant htt protein is found in the inclusions in the brain of the patient suffering from HD, which is the pathological hallmark of the disease1. Exon-1 of htt comprises of 17 amino acid long N-terminal helix (Nt17), polyQ tract in between and polyP-rich C-terminal. Nt17 has been reported to selfassociate and enhance the rate of mutant htt aggregation which leads to protein aggregation resulting in the inclusion formation. The lysine residues K6 and K15 in Nt17 are thought to be involved in inter helical association and are proposed to form the template for initial oligomerization2. To prevent these specific residues from interacting, we have utilized a lysine specific molecular tweezer (MT) 3. Here, we have studied the effect of MT on the structure and oligomerization process of the mutant htt. By MD...