Dataset Information

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins.

ABSTRACT: The HIV-1 capsid is a shell that encapsulates viral RNA, and forms a conical structure by assembling oligomers of capsid (CA) proteins. Since the CA proteins are highly conserved among many strains of HIV-1, the inhibition of the CA function could be an appropriate goal for suppression of HIV-1 replication, but to date, no drug targeting CA has been developed. Hydrophobic interactions between two CA molecules through Trp184 and Met185 in the protein are known to be indispensable for conformational stabilization of the CA multimer. In our previous study, a small molecule designed by in silico screening as a dipeptide mimic of Trp184 and Met185 in the interaction site was synthesized and found to have significant anti-HIV-1 activity. In the present study, molecules with different scaffolds based on a dipeptide mimic of Trp184 and Met185 have been designed and synthesized. Their significant anti-HIV activity and their advantages compared to the previous compounds were examined. The present results should be useful in the design of novel CA-targeting anti-HIV agents.

SUBMITTER: Kobayakawa T

PROVIDER: S-EPMC9834766 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins.

Kobayakawa Takuya T Yokoyama Masaru M Tsuji Kohei K Fujino Masayuki M Kurakami Masaki M Onishi Takato T Boku Sayaka S Ishii Takahiro T Miura Yutaro Y Shinohara Kouki K Kishihara Yuki Y Ohashi Nami N Kotani Osamu O Murakami Tsutomu T Sato Hironori H Tamamura Hirokazu H

RSC advances 20230112 3

The HIV-1 capsid is a shell that encapsulates viral RNA, and forms a conical structure by assembling oligomers of capsid (CA) proteins. Since the CA proteins are highly conserved among many strains of HIV-1, the inhibition of the CA function could be an appropriate goal for suppression of HIV-1 replication, but to date, no drug targeting CA has been developed. Hydrophobic interactions between two CA molecules through Trp184 and Met185 in the protein are known to be indispensable for conformation ...[more]

PMID: 36712613

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Project description:Proteins with molecular weights of <25 kDa are involved in major biological processes such as ribosome formation, stress adaption (e.g., temperature reduction) and cell cycle control. Despite their importance, the coverage of smaller proteins in standard proteome studies is rather sparse. Here we investigated biochemical and mass spectrometric parameters that influence coverage and validity of identification. The underrepresentation of low molecular weight (LMW) proteins may be attributed to the low numbers of proteolytic peptides formed by tryptic digestion as well as their tendency to be lost in protein separation and concentration/desalting procedures. In a systematic investigation of the LMW proteome of Escherichia coli, a total of 455 LMW proteins (27% of the 1672 listed in the SwissProt protein database) were identified, corresponding to a coverage of 62% of the known cytosolic LMW proteins. Of these proteins, 93 had not yet been functionally classified, and five had not previously been confirmed at the protein level. In this study, the influences of protein extraction (either urea or TFA), proteolytic digestion (solely, and the combined usage of trypsin and AspN as endoproteases) and protein separation (gel- or non-gel-based) were investigated. Compared to the standard procedure based solely on the use of urea lysis buffer, in-gel separation and tryptic digestion, the complementary use of TFA for extraction or endoprotease AspN for proteolysis permits the identification of an extra 72 (32%) and 51 proteins (23%), respectively. Regarding mass spectrometry analysis with an LTQ Orbitrap mass spectrometer, collision-induced fragmentation (CID and HCD) and electron transfer dissociation using the linear ion trap (IT) or the Orbitrap as the analyzer were compared. IT-CID was found to yield the best identification rate, whereas IT-ETD provided almost comparable results in terms of LMW proteome coverage. The high overlap between the proteins identified with IT-CID and IT-ETD allowed the validation of 75% of the identified proteins using this orthogonal fragmentation technique. Furthermore, a new approach to evaluating and improving the completeness of protein databases that utilizes the program RNAcode was introduced and examined.

Dataset Information

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins.

Publications

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins.

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