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Receptor modification as a therapeutic approach against viral diseases.

ABSTRACT: Poliovirus causes flaccid paralysis through the destruction of motor neurons in the CNS. Susceptibility to its infection is mainly due to the interaction in between the surface capsid proteins and its receptors on the host cell surface, important for binding, penetration and other necessary events during early infection. Receptor modification is a new approach to treat viral diseases by the modification of target proteins structure. Binding domains are modified in an effective way to make it difficult for the virus to recognize it. In this study, tolerant and intolerant induced mutations in the poliovirus receptor, VP1 and VP2 were identified and substituted in the seed sequence to get the modified versions. Substitutions causing changes in initial folding were short listed and further analyzed for high level folding, physiochemical properties and interactions. Highest RMSD values were observed in between the seed and the mutant K90F (3.265 Å) and Q130W (3.270Å) respectively. The proposed substitutions were found to have low functional impact and thus can be further tested and validated by the experimental researchers. Interactions analyses proved most of the substitutions having decreased affinity for both the VP1 and VP2 and thus are of significant importance against poliovirus. This study will play an important role for bridging computational biology to other fields of applied biology and also will provide an insight to develop resistance against viral diseases. It is also expected that same approach can also be applicable against other viruses like HCV, HIV and other in near future.

SUBMITTER: Farid R

PROVIDER: S-EPMC3338978 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:For more than 20 years, drug discovery has relied on two assumptions, i.e. (i) a therapeutic response can be triggered by modulating the activity of a single gene product, and (ii) a compound uncovered by its activity on a recombinant protein in vitro can perform its activity in vivo. Drug discovery operates accordingly by using the concepts of targets and pipelines. The target, such as a gene product, is the intended point of therapeutic intervention, and compounds that modulate its activity in vitro follow a series of downstream developments. This reductionist approach has developed due to advances in combinatorial chemistry, robotics, molecular biology, and genomics. The expectation of this approach is that the frequency of drug discovery will dramatically increase, while its associated cost would decrease. However, the frequency of new drug discovery has decreased, while the associated costs have surged. We performed a retrospective study that examined how successful development programs have led to marketed drugs for all indications except anti-infective and anti-neoplastic agents. We concluded that the target and pipeline paradigms are limited and are actually causing the drug development industry to collectively fail to meet the critical medical needs. Impact statement The initial scope of this investigation was to build the set of human genes that are presumed to be the therapeutic intervention points of US FDA-approved drugs, in all therapeutics areas but oncology. The prerequisite for this study was the establishment of the non-redundant set of all active pharmaceutical ingredients for these disease areas. Pertaining to complex diseases, the main observation was that there is not a single instance in the history of drug discovery, where a compound, initially selected by means of a biochemical assay, achieved a significant therapeutic response. The whole field of Drug R&D faces an unacceptable lack of new treatments to address unmet medical needs. The conclusion is that complex biological assays have to be designed for the primary selection of candidate therapeutics.

Project description:BackgroundTargeted immunotherapy is mostly associated with cancer treatment wherein designed molecules engage signaling pathways and mutant proteins critical to the survival of the cell. One of several genetic approaches is the use of in silico methods to develop immune epitopes targeting specific antigenic regions on related mutant proteins. In a recent study we showed a functional association between the gamma retrovirus HERV-H Long Terminal Associating (HHLA1, HHLA2 and HHLA3) proteins and melanoma associated antigen of the B class proteins (MAGEB5), with a resultant decrease in expression of HLA class I and II immune variants. HLA-C and HLA-DRB5 were the main HLA class I and II Immune variants, respectively, that showed expression changes across viral samples of interest. Specific immune variants for HLA-C and HLA-DRB5 were filtered for the top ten based on their relative frequency of counts across the samples.ResultsProtein variants for HHLA1, HHLA2, HHLA3 and MAGEB5 were used to predict antigenic epitope peptides to immune peptide-MHC class I and II binding using artificial neural networks. For IC50 peptide scores (PS) ≥ 0.5 with a transformed binding ability between 0 and 1, the top 5 epitopes identified for all targeted genes HHLA1,2 & 3 and MAGEB5 were qualified as strong or weak binders according to the threshold. Domain analysis using NCBI Conserved Domain Database (CDD) identified HHLA2 with immunoglobulin-like domains (Ig_C1-set) and MAGEB5 with the MAGE Homology Domain (MHD). Linear regression showed a statistical correlation (P < 0.001) for HHLA2 and MAGEB5 predicted epitope peptides to HLA-C but not HLA-DRB5. The prediction model identified HLA-C variant 9 (HLA-C9, BAA08825.1 HLA-B*1511) at 1.1% as the most valuable immune target for clinical considerations. Identification of the 9-mer epitope peptide within the domain showed for HHLA2: YANRTSLFY (PS = 0.5837) and VLAYYLSSSQNTIIN (PS = 0.77) for HLA-C and HLA-DRB5, respectively and for MAGEB5, peptides: FVRLTYLEY (PS = 0.5293) and YPAHYQFLWGPRAYT (PS = 0.62) for HLA-C and HLA-DRB5, respectively.ConclusionSpecific immune responses to targeted epitope peptides and their prediction models, suggested co-expression and co-evolution for HHLA2 and MAGEB5 in viral related diseases. HHLA2 and MAGEB5 could be considered markers for virus related tumors and targeted therapy for oncogenic diseases.

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Receptor modification as a therapeutic approach against viral diseases.

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