Protein-protein interactions (PPIs) are responsible for the regulation of a variety of important functions within living organisms. Compounds which can selectively modulate aberrant PPIs are novel therapeutic candidates for treating human diseases. Whilst PPIs have traditionally been considered as "undruggable", research in this area has led to the emergence of several effective methodologies for targeting PPIs. One such methodology is peptide stapling, which involves constraining a short peptide into its native alpha-helical form by forming a covalent link between two of its amino acid side-chains. The Sondheimer dialkyne reagent has previously been used in strain-promoted double-click cycloadditions with diazidopeptides to generate stapled peptides that are capable of inhibiting PPIs. However, the Sondheimer dialkyne suffers from poor water-solubility; it decomposes rapidly in aqueous solutions which limits its application in biological systems. This dissertation describes the design and synthesis of new substituted variants of the Sondheimer dialkyne with increased solubility and stability, that are suitable for application in strain promoted double click peptide stapling. In total, ten different derivatives were generated; of these, a meta-trimethylammonium substituted variant was found to have particularly high water-solubility and aqueous stability, as well as high azide reactivity. The substituted Sondheimer dialkynes were applied to the strain promoted double click stapling of p53-based diazido peptides in an effort to generate stapled peptide-based inhibitors of the oncogenic p53 MDM2 PPI, a validated target for anticancer therapeutics. Three stapled peptides were found to have inhibitory activity, thus demonstrating the utility of the novel dialkynes in the preparation of PPI inhibitors. The functionalised stapled peptide formed from a meta-fluoro substituted Sondheimer dialkyne was found to be the most potent inhibitor. All ortho-substituted Sondheimer dialkynes were found to be unreactive, whereas those with a meta-trimethylammonium substituent were highly reactive when compared to other meta-substituted dialkynes. These patterns in azide reactivity could be explained through X-ray crystallographic studies and density functional theory calculations.

Le virus respiratoire syncytial (VRS) est le principal agent responsable desbronchopneumonies du jeune veau et des bronchiolites du nourrisson. Il n’existe pas devaccin ni d’antiviraux spécifiques pour l’homme. La réplication du génome et la transcriptiondes gènes viraux sont assurées par un ensemble de protéines virales constituant le complexeARN polymérase ARN-dépendant : la nucléoprotéine N, la phosphoprotéine P, le facteur detranscription M2-1 et la grosse sous-unité L. L’objectif principal de ma thèse était d’obtenirde nouvelles données structurales et fonctionnelles sur le complexe ARN-polymérase ARNdépendante(RdRp) du VRS, en particulier sur le couple P-L. Pour ceci j’ai tout d’aborddéveloppé un protocole de production et purification de la protéine L sous formerecombinante en cellules d’insecte. Ceci m’a permis ensuite de cartographier le sited’interaction de P avec L. J’ai ainsi mis en évidence que la protéine L interagit avec la partieC-terminale de la protéine P, au-niveau des résidus 216 à 239. Les données obtenuessuggèrent que ce domaine peut former un nouvel élément de reconnaissance moléculaire(« MoRE ») se structurant en hélice alpha lors de l’interaction avec la protéine L. De plus, lacartographie de ce domaine d’interaction m’a permis d’identifier entre les résidus 164 et 205de P une nouvelle région impliquée dans le recrutement de la protéine L aux corpsd’inclusions viraux. Ces nouvelles données ouvrent la voie à de nouvelles études structuralesde l’ARN-polymérase du VRS et nous permettent d’envisager de nouvelles stratégiesantivirales ciblant ce complexe. / Respiratory syncytial virus (RSV) is the leading cause of calves bronchopneumonia andinfants bronchiolitis. Neither vaccine nor antiviral treatments are currently available for use inhumans. Viral genome is replicated and transcribed by a set of viral proteins constituting theviral RNA-dependent RNA polymerase (RdRp) complex: the nucleoprotein (N), thephosphoprotein (P), the transcription factor (M2-1) and the large subunit (L). This workaimed to unveil new structural and functional data regarding the viral RdRp, especially the PLcouple. With this aim in view, I have first conceived a protocol to produce and purifyrecombinant L and P proteins expressed in insect cells. This tool enabled the fine mappingand characterization of the L binding domain of the RSV phosphoprotein. This highlightedthe interaction between the L protein and the C-terminal region of the P protein, especiallyresidues 216 to 239. Further data suggests that this area constitutes an alpha helix formingmolecular recognition element (« MoRE ») during P-L interaction. Furthermore, this studyunveiled a new region of the P protein encompassing residues 164 to 205, involved in therecruitment of L protein to viral inclusion bodies. These new results open the way toupcoming structural studies of RSV RdRp and allow us to define a new target for thedevelopment of antiviral drugs against RSV.

Domínio proteico é uma sequência de aminoácidos evolutivamente conservada e funcionalmente independente. Um dos aspectos mais importantes do estudo de uma proteína que contem múltiplos domínios é o entendimento da comunicação, entre os diferentes domínios, e seu papel biológico. Essa comunicação em maior parte é feita pela interação direta entre domínios. A interação poderia ser tratada como uma clássica interação proteína-proteína. Entretanto, proteínas multidomínio possuem restrições determinadas por suas regiões conectoras. Os conectores interdomínio impõem restrições e limitam espaço conformacional dos domínios. Apresentamos aqui o MAD, uma rotina capaz de obter modelos tridimensionais de alta resolução para proteínas, contendo qualquer número de domínios, a partir de sua sequencia primária. Os domínios conservados são identificados utilizando a base de domínios conservados (CDD) e seus limites são utilizados para definir as regiões conectoras. É criado um ensamble de possíveis dobramentos dos conectores e sua distribuição de distâncias C/N-terminais são utilizadas como restrição espacial na busca pela interação entre os domínios.Os modelos dos domínios são obtidos por uma modelagem comparativa. Foi implementada uma heurística, capaz de lidar com a natureza combinatorial dos múltiplos domínios e com a necessidade imposta pela limitação computacional de realizar o docking dos domínios em forma de pares. Todas combinações de domínios são submetidas as rotinas de docking. Aplica-se filtro de distância e energético, excluindo as conformações que apresentam distância C/N-terminal entre domínios maior do que o valor máximo observado no ensamble de conectores e seleciona as conformações energeticamente mais favoráveis. As conformações são submetidas a uma rotina de agrupamento hierárquico baseada em sua similaridade estrutural. Para a segunda fase as conformações selecionadas são pareadas com seu domínio complementar e ressubmetidas a rotina de docking até que todas as fases tenham sido completadas. Foi criado um conjunto de testes a partir do Protein Data Bank contendo 54 proteínas multidomínio para que a rotina de docking do MAD fosse comparada com outros softwares utilizados pela comunidade cientifica, mostrou-se superior ou equivalente aos métodos testados. A capacidade de utilizar dados experimentais foi demostrada através da proposição de um modelo da forma ativa da enzima tirosina fosfatase 2, nunca observado experimentalmente. A rotina de docking foi expandida paralelamente em uma aplicação standalone e utilizada na resolução de diversos problemas biológicos. Concluímos que a inovação metodológica proposta pelo MAD é de grande valia para a modelagem molecular e tem potencial de gerar uma nova perspectiva a respeito da interação de proteína multidomínio, visto que é possível analisar essas proteínas em sua plenitude e não como domínios separados. / Protein domain is an evolutionary conserved and functionally independent amino acid sequence. One of the most important aspects of the study of a protein that contains multiple domains is the understanding of communication between the different areas, and their biological role. This communication is made mostly by direct interaction between domains. The interaction could be treated as a classical protein-protein interaction. However, multidomain proteins have certain restrictions for its connector regions. The intra connectors impose restrictions and limit conformational space of the domains. We present the MAD, a routine able to get three-dimensional models of high-resolution protein, containing any number of domains, from its primary sequence. The conserved domains are identified using the basic conserved domains database (CDD) and its boundaries are used to define the connector regions. This creates a ensemble of possible folding of the connectors and distribution of distances C/N-terminals are used as spatial restriction in the search for interaction between domains.Os models of the domains are obtained by comparative modelling. A heuristic able to handle the combinatorial nature of the multiple areas and the need imposed by the computer to perform the limitation of the docking areas as pairs was implemented. All combinations of domains are referred to the docking routines. Distance and energy filters are applied, excluding conformations that have C/N-terminal domains distances larger than the maximum value observed in the connectors ensemble and selects the most favourable energy conformations. Conformations are subjected to hierarchical clustering routine based on their structural similarity. For the second phase, the selected conformations are paired with its complementary domain and resubmitted to the docking routine until all phases have been completed. A test set has been created from the Protein Data Bank containing 54 multidomain proteins so that the docking routine of MAD could be compared with other software used by the scientific community, it has been shown to be superior or equivalent to the tested methods. The ability to use experimental data was demonstrated by proposing a model of the active form of tyrosine phosphatase enzyme 2, never observed experimentally. The docking routine was expanded in a standalone application and used in solving various biological problems. We conclude that the methodological innovation proposed by the MAD is very useful for molecular modelling and has the potential to generate a new perspective on multidomain protein interaction as you can analyse these proteins in its entirety and not as separate domains.

Avec 8,8 millions de décès dénombrés en 2015, le cancer est l’une des plus grandes causes de mortalité dans le monde. De nouvelles stratégies thérapeutiques ont émergé et l’identification de nouvelles cibles biologiques comme notamment la protéine Asf1, un chaperon d’histone H3-H4 surexprimée dans les cellules cancéreuses et en particulier le cancer du sein. Cette protéine possède différentes fonctions dans la cellule et agit à plusieurs endroits par des interactions protéine-protéines. Au cours de cette thèse de doctorat, nous avons développé une stratégie originale de design d’inhibiteurs d’interactions protéine-protéine avec des foldamères peptidomimes à base d’urées. Ces foldamères ont 1) la capacité de se replier en hélice 2,5, rappelant les hélices α des peptides et 2) d’être hautement tolérés et initiateurs d’hélicité lorsqu’ils sont conjugués à des fragments peptidiques. Nous avons développé des oligomères mixtes comprenant une alternance de segment(s) peptidique(s) et multi-urée, appelées chimères, ayant l’avantage de combiner la reconnaissance naturelle de peptides et la forte propension des oligourées à former des hélices stables. Après une étude structurale montrant qu’avec l’insertion d’un court segment à base d’urées dans un peptide hydrosoluble adoptant une conformation en hélice  la conformation hélicoïdale pour une majorité des chimères est conservée, des composés mimant la partie hélicoïdale C-terminale de l’histone H3 ont été élaborés. Une interaction de l’ordre du micromolaire avec Asf1 a été observée en solution puis validée à l’état solide par cristallographie aux rayons X. En vue d’optimiser la reconnaissance de ces chimères avec la surface d’Asf1 et leur sélectivité, un panel de modifications a été réalisée (i.e. séquence primaire, longueur du segment urée). Nous avons ainsi conçu des chimères α/urée possédant des affinités de liaison pour Asf1 comprises entre le nano- et micromolaire. Le composé le plus prometteur a été internalisé avec succès dans des cellules cancéreuses après conjugaison bioreductible avec un peptide vecteur et pourrait conduire à la mort cellulaire de la lignée tumorale étudiée. / In 2015, 8.8 million of death were due to cancer making it an important cause of death in the world. The necessity to develop new anticancer treatments led to the search and discovery of new biological targets, such as Asf1, a histone chaperone protein of H3-H4 which is overexpressed in cancer cells, in particular in breast cancer. This protein plays a role in different biological processes in cells through protein-protein interactions (PPIs). During this thesis, we developed an original strategy to design inhibitors of PPIs with urea-based peptidomimetics. These foldamers are able to fold into stable 2.5-helix reminiscent to the natural α-helix. Designed urea-based foldamers have been synthesized as hybrid oligomers consisting of α-peptide and oligourea segments. With a combination of the two backbones, these compounds named “chimeras” presents advantages of both species with the natural recognition of α-peptides and the innate helical stability of oligourea. First, a model study was performed to evaluate the impact of the introduction of short urea segments into a long water-soluble peptide. Circular dichroism experiments confirmed that the helical conformation was conserved. New series of compounds that mimic a helical part of H3 were synthesized and their interaction with Asf1 was studied in solution and in solid state using a range of biophysical methods. Several modifications into the sequence were performed (side chain substitution, size of the urea segment or compound) in order to improve the recognition of Asf1 surface as well as their selectivity. We conceived oligourea-peptide chimeras with affinity for Asf1 in the micromolar range. Our best compound linked to a cell penetrating peptide was shown to enter into cells and to induce cell death.

As metaloproteases AAA/FtsH são componentes chave do controle da qualidade das proteínas inseridas nas membranas de mitocôndrias e cloroplastos. Em Arabidopsis thaliana, as proteases FtsH presentes nas membranas dos tilacóides formam um complexo heterohexamérico composto pelas subunidades FtsH1/FtsH5 (tipo A) e FtsH2/FtsH8 (tipo B). Este complexo está envolvido na reciclagem de proteínas foto-danificadas, especialmente da proteína D1, centro de reação do PSII. Algumas linhas de evidências indicam ainda que existe um limiar de concentração das proteases FtsH, necessário para a correta formação e desenvolvimento dos cloroplastos. Apesar da extensiva caracterização genética e molecular das proteases FtsH, o mecanismo regulatório do complexo FtsH dos cloroplastos não foi totalmente elucidado até o momento, contudo existem evidências de que a sua ativação pode estar relacionada a alta incidência luminosa e a outras condições de estresse. A presença de fatores proteicos auxiliares, foi testada como hipótese alternativa por nosso grupo, através do uso da protease FtsH5 como isca em um ensaio de duplo híbrido de leveduras. Este ensaio identificou uma proteína interagente putativa, nomeada FIP (FtsH5 Interacting Protein), a qual comprovadamente interage com FtsH5 e está localizada nas membranas dos tilacóides. De modo a investigar o papel regulatório putativo de FIP sobre a atividade do complexo FtsH, nós analisamos os padrões de expressão em uma ampla gama de condições de estresse a partir de dados públicos de microarranjos de DNA. Os perfis de expressão indicam que FIP pode ser um regulador negativo da atividade do complexo. Os resultados também sugerem que o complexo pode estar envolvido na resposta do cloroplasto a diferentes tipos de condições de estresse. O estudo da história evolutiva das proteínas interagentes FtsH5 e FIP evidenciou que as sequências homólogas a FIP são encontradas exclusivamente em musgos e plantas superiores, sugerindo assim que a origem de FIP pode estar relacionada a colonização terrestre. Todos os genes codificantes das proteases FtsH do complexo foram usados como \"query\" na busca por sequências homólogas, permitindo a classificação das proteases FtsH nos tipos A e B por inferência filogenética Bayesiana. Análises filogenéticas Bayesianas também foram feitas para FIP e as proteases FtsH tipos A e B, independentemente. A análise Mirrortree suportou a existência de coevolução entre FIP e as proteases FtsH tipo A. Por outro lado, nenhuma correlação foi encontrada entre FIP e as proteases FtsH tipo B, o que corrobora nossas observações experimentais anteriores. Além disso, o agrupamento portador de homólogos FIP pôde ser recuperado em uma filogenia mais completa das proteases FtsH do tipo A. Análises subsequentes mostraram que ambas as proteínas interagentes estão extensivamente sobre seleção negativa e que proteases FtsH tipo A são bastante conservadas, principalmente nos seus domínios internos. / Eukaryotic AAA/FtsH metalloproteases display a key role in the protein quality control of membrane-inserted proteins in mitochondria and chloroplasts. In Arabidopsis thaliana, chloroplast thylakoidal membranes FtsH proteases form a heterohexameric complex made by FtsH1/FtsH5 (type A) and FtsH2/FtsH8 (type B) subunits. This complex is involved in protein turnover of photo-damaged proteins, in particular the D1 protein at the PSII reaction center. Several lines of evidence also indicate that a FtsH threshold level is necessary for the proper formation and development of chloroplasts. Despite extensive genetic and molecular characterization of the FtsH proteases, the regulatory mechanism of the FtsH complex in chloroplasts has not yet been fully elucidated, however, there are evidences that its activation might be related to high light incidence and other stress conditions. The presence of auxiliary protein factors, as an alternative hypothesis, was tested by our group, through the use of the protease FtsH5 as bait in a yeast two-hybrid assay. This essay identified a putative interacting protein named FIP (FtsH5 Interacting Protein), which has been proved to interact with FtsH5 and be located at the thylakoid membranes. In order to investigate a putative regulatory role of FIP on FtsH complex activity, we analyzed gene expression patterns in a wide range of stress conditions from public DNA microarray data. The expression profiles indicate that FIP could be a negative regulator of the FtsH complex activity. The results also suggest that the complex may be involved in the chloroplast response to different types of stress conditions. In order to shed some light on the evolutionary history of FtsH5 and FIP interacting proteins, we have shown that FIP\'s homologous sequences were exclusively found in mosses and higher plants, suggesting that FIP origin might be related to the plant terrestrial colonization. All Arabidopsis FtsH complex-encoding genes were used as \"query\" sequences in search for homologous sequences, allowing us to classify the FtsH proteases in type A and B by Bayesian phylogenetic inference. Bayesian phylogenetic analyses were also run for FIP and FtsH types A and B proteases, independently. Mirrortree analysis supported coevolution between FIP and type A FtsH proteases. On the other hand, no correlation was found between FIP and type B FtsH homologues, which support our previous experimental observations. In addition, the FIP bearing cluster could be recovered in a more complete type A FtsH phylogeny. Subsequent analyzes have shown that both interacting proteins are extensively under negative selection and that type A FtsH are very conserved, mainly in its inner domains.

PSD-95/Dlg/ZO-1 (PDZ) domain - PDZ binding motif (PBM) interactions have been one of the most well studied protein-protein interaction systems through biochemical, biophysical and high-throughput screening (HTS) strategies. This has allowed us to understand the mechanism of individual PDZ-PBM interactions and the re-engineering of PBMs to bind tighter or to gain or lose certain specificity. However, there are several thousand native PDZ domains whose biological ligands remain unknown. Because of the low sequence identity among PDZ domain homologues, promiscuous binding profiles (defined as a PDZ domain that can accommodate a set of PBMs or a PBM that can be recognized by many PDZ domains), and context-dependent interaction mechanism, we have an inadequate understanding of the general molecular mechanisms that determine the PDZ-PBM specificity. Therefore, predicting PDZ specificity has been elusive. In addition, no de novo PBM ligand or artificial non-native PDZ domain have been successfully designed. This reflects the general challenges in understanding the general principles of PDZ-ligand interactions, namely that they are context-dependent, exhibit weak binding affinity, narrow binding energy range, and larger interaction surface than other protein-ligand interactions. Together, PDZ domains make good model systems to investigate the fundamental principles of protein-protein interactions with a wide spectrum of biomedical implications. My studies suggest that understanding PBM specificity with the set of structural positions forming the binding pocket can connect sequence, structure and function of a PDZ domain in a general context. They also suggest that this way of understanding the specificity will shed light on prediction and engineering of specificity rationally. Structural analysis on most of the available PDZ domain structures was established to support the principle (Chapter I). The principle was tested against two different types of PBM; C-terminal PBM (Chapter II) and internal PBM (Chapter III), and shown to support better understanding and design of PDZ domain specificity. We further applied the principle to design de novo PDZ domains, and the preliminary data hints that it is optimistic to engineer PDZ domain specificity (Appendix A and B).

Drought stress is considered one of the most devastating abiotic stress factors that limit crop productivity for modern agriculture worldwide. There is a large range of physiological and biochemical responses induced by drought stress. The responses range from physiological and biochemical to regulation at transcription and posttranscriptional levels. Post-transcription, the products encoded by eukaryotic genes must undergo a series of modifications to become a mature mRNA. Polyadenylation is an important one in terms of regulation. Polyadenylation impacts gene expression through determining the coding and regulation potential of the mRNA, especially when different mRNAs from the same gene may be polyadenylated at more than one position. This alternative polyadenylation (APA) has numerous potential effects on gene regulation and function. I have studied the impact of drought stress on APA, testing the hypothesis that drought stress may give rise to changes in the usage of poly(A) sites generating different mRNA isoforms. The results showed that usage of poly(A) sites that lie within 5’-UTRs and coding sequence (CDS) changes more than usage of sites in other regions due to drought stress. Alternative polyadenylation is meditated by the polyadenylation complex of proteins that are conserved in eukaryotic cells. The Arabidopsis CPSF30 protein (AtCPSF30), which is an RNA-binding endonuclease subunit of the polyadenylation complex, plays an important role in controlling APA. Previous study showed that poly(A) site choice changes on a large scale in oxidative stress tolerant 6 (oxt6), a mutant lacking AtCPSF30. Within the mutant/WT genotypes, there are three classes of poly(A) site, wild type specific, oxt6 specific, and common (both in wild type and mutant). The wild type specific and oxt6 specific mRNAs make up around 70% of the total of all mRNA species. I hypothesize that the stability of these various mRNA isoforms should be different, and that this is a possible way that AtCPSF30 regulates gene expression. I tested this by assessing the influence poly(A) sites can have on the mRNA isoform’s stability in the wild type and oxt6 mutant. My results show that most mRNA isoforms show similar stability profiles in the wild-type and mutant plants. However, the mRNA isoforms derived from polyadenylation within CDS are much more stable in the mutant than the wild-type. These results implicate AtCPSF30 in the process of non-stop mRNA decay. Messenger RNA polyadenylation occurs in the nucleus, and the subunits of the polyadenylation complex that meditate this process are expected to reside within the nucleus. However, AtCPSF30 by itself localizes not only to the nucleus, but also to the cytoplasm. AtCPSF30 protein contains three predicted CCCH-type zinc finger motifs. The first CCCH motif is the primary motif that is responsible for the bulk of its RNA-binding activity. It can bind with calmodulin, but the RNA-binding activity of AtCPSF30 is inhibited by calmodulin in a calcium-dependent manner. The third CCCH motif is associated with endonuclease activity. Previous studies demonstrated that the endonuclease activity of AtCPSF30 can be inhibited by disulfide reducing agents. These published results suggest that there are proteins that interact with AtCPSF30 and act through calmodulin binding or disulfide remodeling. To test this hypothesis, I screened for proteins that interact with AtCPSF30. For this, different approaches were performed. These screens led me to two proteins-one protein that is tyrosine-phosphorylated and whose phosphorylation state is modulated in response to ABA, which well-known ABA regulates guard cell turgor via a calcium-dependent pathway, and the other is ribosome protein L35(RPL35), which plays an important role in nuclear entry, translation activity, and endoplasmic reticulum(ER) docking. These results suggest that multiple calcium-dependent signaling mechanisms may converge on AtCPSF30, and AtCPSF30 might be directly interact with ribosome protein.

Voltage-gated sodium channels auxiliary subunits evolutionary emerged nearly 500 million years ago during the Cambrian explosion. These subunits alter one the most important ion channels to electrical signaling, the voltage-gated sodium channels support the propagation of electric impulses in animals. The mechanism for the auxiliary subunits effects on the channels is poorly understand, as is the stoichiometry between the auxiliary subunit and the channel. The focus of my thesis is to generate assays and to use these approaches to understand the interactions different types of voltage-gated channels and their auxiliary subunits. A biochemical approach was taken to identify novel interactions between the eukaryotic sodium channel auxiliary subunits and a prokaryotic voltage-gated sodium channel, a protein that diverged from the eukaryotic voltage-gated sodium channels billions of years ago. These interactions between the auxiliary subunits and channels were probed with chemical and photochemical crosslinkers in search of interaction surfaces and similarity to explain the mechanisms of interaction. The work in this thesis identified novel interactions between the voltage-gated sodium channel auxiliary subunits and voltage-gated channels that are distantly related to the voltage-gated sodium channels principally thought to be modulated by the auxiliary subunits. From this work a rudimentary concept can be theorized that the voltage-gated sodium channel β-subunits and not only β1 have a more primary role in electrophysiology by associating with multiple different types of ion channels.

Proteins can be described as the “machineries” responsible for almost all tasks in the levels of organizational complexity in multi-cellular organisms namely: the cells, tissues, organs and systems. Any disorder in the function of a protein at any of these levels could result in disease, and a study of protein function is critical to understanding the pathological features of the disease at the molecular level. A quick glance at these abundantly present proteins reveals two striking features: large diversity of biological function, and the variations in structural complexity, which varies from simple random coils, to turns and helices, and on to structured assemblies of turns, helices and sheets. Over the past few years, more research efforts have been channeled to the application of synthetic research to protein dynamics, most especially in disease conditions. This provides insight into the design and development of chemical tools capable of modulating protein functions .Some of such tools include small molecules, peptides and peptidomimetics. In this work, we have described the application of these tools to three (3) different disease systems topping the list of incurable diseases: HIV, Diabetes, and Cancer. We have designed and developed chemical probes to facilitate a better understanding of major “culprit” proteins underlying the pathological conditions associated with these diseases. Our designed chemical probes were capable of modulating protein functions by producing the desired effects: inhibition of protein-protein interactions.

Peptidomimetics are synthetic foldamers that expected more resistant to proteolytic degradation and enormous chemodiversity when compared with peptides. To date, the functional peptidomimetics such as β-peptides, peptoids, oligoureas, etc have been developed in many science fields. In order to explore the unnatural foldameric architectures, it’s necessary to discover the novel frameworks and molecular scaffolds. γ-AApeptides were reported to be a new class of peptidomimetics that showed its potential applications in drug discovery and chemical biology. However, a wide function and property of γ-AApeptides need to be further explored. To expand the potential application of γ-AApeptides in biochemistry, I have been focusing on the development of bioactive peptidomimetics, such as exploring the antibacterial activity of helical 1:1 α-sulfono-γ-AA heterogeneous peptides, developing the helical peptidomimetic as the inhibitor of the protein Ras_Raf interaction, identifying the protein/peptide ligands by the novel one-bead-two compound macrocyclic γ-AApeptide screening library, and elucidating the de novo dragon-boat-shaped synthetic foldamers.