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1.
Bioorg Chem ; 129: 106204, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36306699

RESUMO

The renin-angiotensin system (RAS) is a key regulator of human arterial pressure. Several of its effects are modulated by angiotensin II, an octapeptide originating from the action of angiotensin-I converting enzyme (ACE) on the decapeptide angiotensin-I. ACE possess two active sites (nACE and cACE) that have their own kinetic and substrate specificities. ACE inhibitors are widely used as the first-line treatment for hypertension and other heart-related diseases, but because they inactivate both ACE domains, their use is associated with serious side effects. Thus, the search for domain-specific ACE inhibitors has been the focus of intense research. Angiotensin (1-7), a peptide that also belongs to the RAS, acts as a substrate of nACE and an inhibitor of cACE. We have synthetized 15 derivatives of Ang (1-7), sequentially removing the N-terminal amino acids and modifying peptides extremities, to find molecules with improved selectivity and inhibition properties. Ac-Ang (2-7)-NH2 is a good ACE inhibitor, resistant to cleavage and with improved cACE selectivity. Molecular dynamics simulations provided a model for this peptide's selectivity, due to Val3 and Tyr4 interactions with ACE subsites. Val3 has an important interaction with the S3 subsite, since its removal greatly reduced peptide-enzyme interactions. Taken together, our findings support ongoing studies using insights from the binding of Ac-Ang (2-7)-NH2 to develop effective cACE inhibitors.


Assuntos
Angiotensina I , Peptidil Dipeptidase A , Humanos , Peptidil Dipeptidase A/metabolismo , Angiotensina I/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Peptídeos/farmacologia
2.
Gene ; 443(1-2): 12-21, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19463923

RESUMO

Immune evasion by Plasmodium falciparum is favored by extensive allelic diversity of surface antigens. Some of them, most notably the vaccine-candidate merozoite surface protein (MSP)-1, exhibit a poorly understood pattern of allelic dimorphism, in which all observed alleles group into two highly diverged allelic families with few or no inter-family recombinants. Here we describe contrasting levels and patterns of sequence diversity in genes encoding three MSP-1-associated surface antigens of P. falciparum, ranging from an ancient allelic dimorphism in the Msp-6 gene to a near lack of allelic divergence in Msp-9 to a more classical multi-allele polymorphism in Msp-7. Other members of the Msp-7 gene family exhibit very little polymorphism in non-repetitive regions. A comparison of P. falciparum Msp-6 sequences to an orthologous sequence from P. reichenowi provided evidence for distinct evolutionary histories of the 5' and 3' segments of the dimorphic region in PfMsp-6, consistent with one dimorphic lineage having arisen from recombination between now-extinct ancestral alleles. In addition, we uncovered two surprising patterns of evolution in repetitive sequence. First, in Msp-6, large deletions are associated with (nearly) identical sequence motifs at their borders. Second, a comparison of PfMsp-9 with the P. reichenowi ortholog indicated retention of a significant inter-unit diversity within an 18-base pair repeat within the coding region of P. falciparum, but homogenization in P. reichenowi.


Assuntos
Antígenos de Protozoários/genética , Evolução Molecular , Proteínas de Membrana/genética , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Alelos , Animais , Sequência de Bases , Proteínas de Membrana/química , Dados de Sequência Molecular , Plasmodium/genética , Plasmodium/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/química , Alinhamento de Sequência
3.
Exp Physiol ; 92(1): 139-45, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17259301

RESUMO

Adenosine triphosphate acts as a fast excitatory neurotransmitter by binding to and activating seven structurally related subtypes of purinergic P2X receptors, which act as ligand-gated ion channels. Besides its role in neurotransmission, ATP also has trophic functions during development of the neuronal system. P2X receptor expression, mainly of P2X(4) and P2X(6) subtypes, has been detected in adult brain and also during neuronal development. We have used the mouse teratocarcinoma P19 cell line as an in vitro model to study P2X(6) receptor expression during early neuronal differentiation. We have detected a full-length and an alternatively spliced form of the mouse P2X(6) receptor gene in P19 cells using reverse transcriptase-polymerase chain reaction. The alternatively spliced form was already present at the stage of pluripotent undifferentiated P19 cells, and was predominant compared to the full-length form during the whole course of neuronal differentiation of P19 cells. Alternative splicing of P2X(6) receptor subunits was also confirmed during postnatal development of mouse brain. During postnatal development, however, the full-length form was predominant compared to the spliced form. Alternative splicing is suggested to regulate P2X(6) receptor function during neuronal differentiation.


Assuntos
Processamento Alternativo , Encéfalo/metabolismo , Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Neurônios/metabolismo , Receptores Purinérgicos P2/metabolismo , Envelhecimento/metabolismo , Animais , Sequência de Bases , Encéfalo/citologia , Encéfalo/embriologia , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Neurônios/citologia , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Purinérgicos P2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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